Publications by authors named "Yanhua Zheng"

75 Publications

Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of lipid droplets.

Mol Cell 2021 07 1;81(13):2722-2735.e9. Epub 2021 Jun 1.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China; Zhejiang University Cancer Center, Hangzhou, 310029, China. Electronic address:

Lipid droplets are important for cancer cell growth and survival. However, the mechanism underlying the initiation of lipid droplet lipolysis is not well understood. We demonstrate here that glucose deprivation induces the binding of choline kinase (CHK) α2 to lipid droplets, which is sequentially mediated by AMPK-dependent CHKα2 S279 phosphorylation and KAT5-dependent CHKα2 K247 acetylation. Importantly, CHKα2 with altered catalytic domain conformation functions as a protein kinase and phosphorylates PLIN2 at Y232 and PLIN3 at Y251. The phosphorylated PLIN2/3 dissociate from lipid droplets and are degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation, and brain tumor growth. In addition, levels of CHKα2 S279 phosphorylation, CHKα2 K247 acetylation, and PLIN2/3 phosphorylation are positively correlated with one another in human glioblastoma specimens and are associated with poor prognosis in glioblastoma patients. These findings underscore the role of CHKα2 as a protein kinase in lipolysis and glioblastoma development.
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http://dx.doi.org/10.1016/j.molcel.2021.05.005DOI Listing
July 2021

Subchronic Oral Toxicity Study of Genetically Modified Rice Rich in β-Carotene in Wistar Rats.

Int J Environ Res Public Health 2021 05 21;18(11). Epub 2021 May 21.

Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China.

(1) Background: a hybrid black rice rich in β-carotene carrying the and genes (HJM) was evaluated in Wistar rats by a 90-day feeding study, aiming to assess its dietary safety. (2) Methods: the HJM rice and its parental line HS were included in rats' diets at levels of 73.5% and 75.5%, respectively. The AIN-93 diet was administered as a nutritional control. No adverse effects on animal behavior or weight gain were observed during the study. Blood samples were collected and analyzed, and standard hematological and biochemical parameters were compared. (3) Results: Some parameters were found to be significantly different, though they remained within the normal range for rats of this breed and age. In addition, upon sacrifice, various organs were weighed, and macroscopic and histopathological examinations were performed, with only minor changes to report. (4) Conclusions: HJM rice exhibited no adverse or toxic effects in Wistar rats in this 90-day study.
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http://dx.doi.org/10.3390/ijerph18115526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196761PMC
May 2021

Two generation reproduction toxicity study of GmDREB3 gene modified wheat in Wistar rats.

Food Chem Toxicol 2021 Jul 29;153:112310. Epub 2021 May 29.

Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan, 430079, China. Electronic address:

To study reproductive toxicity of gene modified wheat generated by introducing DREB3 (drought response element binding protein 3) gene, Wistar rats of were allocated into 3 groups and fed with DREB3 gene modified wheat mixture diet (GM group), non-gene modified wheat mixture diet (Non-GM group) and AIN-93 diet (Control group) from parental generation (F0) to the second offspring (F2). GM wheat and Non-GM wheat, Jimai22, were both formulated into diets at a ratio of 69.55% according to AIN93 diet for rodent animals. Compared with non-GM group, no biologically related differences were observed in GM group rats with respect to reproductive performance such as fertility rate, gestation rate, mean duration, hormone level, reproductive organ pathology and developmental parameters such as body weight, body length, food consumption, neuropathy, behavior, immunotoxicity, hematology and serum chemistry. In conclusion, no adverse effect were found relevant to GM wheat in the two generation reproduction toxicity study, indicating the GM wheat is a safe alternative for its counterpart wheat regarding to reproduction toxicity.
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http://dx.doi.org/10.1016/j.fct.2021.112310DOI Listing
July 2021

Brassinosteroids inhibit miRNA-mediated translational repression by decreasing AGO1 on the endoplasmic reticulum.

J Integr Plant Biol 2021 May 21. Epub 2021 May 21.

State Key Laboratory of Genetic Engineering, Ministry of Education Key Laboratory of Biodiversity Sciences and Ecological Engineering, Collaborative Innovation Center of Genetics and Development, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Translational repression is a conserved mechanism in microRNA (miRNA)-guided gene silencing. In Arabidopsis, ARGONAUTE1 (AGO1), the major miRNA effector, localizes in the cytoplasm for mRNA cleavage and at the endoplasmic reticulum (ER) for translational repression of target genes. However, the mechanism underlying miRNA-mediated translational repression is poorly understood. In particular, how the subcellular partitioning of AGO1 is regulated is largely unexplored. Here, we show that the plant hormone brassinosteroids (BRs) inhibit miRNA-mediated translational repression by negatively regulating the distribution of AGO1 at the ER in Arabidopsis thaliana. We show that the protein levels rather than the transcript levels of miRNA target genes were reduced in BR-deficient mutants but increased under BR treatments. The localization of AGO1 at the ER was significantly decreased under BR treatments while it was increased in the BR-deficient mutants. Moreover, ROTUNDIFOLIA3 (ROT3), an enzyme involved in BR biosynthesis, co-localizes with AGO1 at the ER and interacts with AGO1 in a GW motif-dependent manner. Complementation analysis showed that the AGO1-ROT3 interaction is necessary for the function of ROT3. Our findings provide new clues to understand how miRNA-mediated gene silencing is regulated by plant endogenous hormones.
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http://dx.doi.org/10.1111/jipb.13139DOI Listing
May 2021

Subchronic oral toxicity study of rhubarb extract in Sprague-Dawley rats.

Regul Toxicol Pharmacol 2021 Jul 21;123:104921. Epub 2021 Apr 21.

Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China. Electronic address:

Objective: The study was primarily used to evaluate subchronic oral toxicity of rhubarb extract.

Methods: The rhubarb extract was orally administered to rats at doses of 0.00, 0.65, 1.62 and 4.05 g/kg BW/day for 13 weeks with a recovery period of 4 weeks. The weight and the relative organ weight of the kidney in the 0.65 g/kg BW group were significantly increased but no significant changes were seen in renal histopathology. When the rats received rhubarb extract at 1.62 g/kg BW or above, the relative weight of the spleen and kidney were significantly increased; the kidney was also swollen and black with hydronephrosis. Histologic examination showed that there was an obvious increase in pigment deposition in renal tubular epithelial cells. No toxic related changes were observed in the 0.65 g/kg BW group, even though organ weight was increased and relative ratio to body weight of kidney were observed at 0.65 g/kg BW dosage, no significant renal histopathologic changes were detected at this dose. Based on the current study conditions and results, the no observed adverse effect level (NOAEL) of rhubarb extract in rats is 0.65 g/kg BW/day.
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http://dx.doi.org/10.1016/j.yrtph.2021.104921DOI Listing
July 2021

Silencing of UCA1 Protects Against MPP-Induced Cytotoxicity in SK-N-SH Cells via Modulating KCTD20 Expression by Sponging miR-423-5p.

Neurochem Res 2021 Apr 19;46(4):878-887. Epub 2021 Jan 19.

Department of Neurology, Weifang Brain Hospital, No. 553, Dongfeng West Street, Weicheng District, Weifang, 261021, Shandong, China.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been implicated in PD development. Nevertheless, little insight has been gained on the mechanisms of UCA1 in PD pathogenesis. The levels of UCA1, miR-423-5p and potassium channel tetramerization domain containing 20 (KCTD20) were assessed by qRT-PCR and western blot. Cell viability was gauged by the CCK-8 assay, and cell apoptosis was detected by flow cytometry. Targeted relationships among UCA1, miR-423-5p and KCTD20 were verified by dual-luciferase reporter and RNA immunoprecipitation assays. Our data showed that MPP induced UCA1 expression in SK-N-SH cells. UCA1 silencing protected against MPP-evoked cytotoxicity in SK-N-SH cells. UCA1 functioned as a miR-423-5p sponge, and the protective impact of UCA1 silencing on MPP-evoked cytotoxicity was mediated by miR-423-5p. KCTD20 was a direct target of miR-423-5p, and miR-423-5p overexpression mitigated MPP-triggered cell injury by down-regulating KCTD20. Furthermore, UCA1 regulated KCTD20 expression by acting as a sponge of miR-423-5p in SK-N-SH cells. Our study first identified that the silencing of UCA1 protected SK-N-SH cells from MPP-evoked cytotoxicity at least in part by targeting the miR-423-5p/KCTD20 axis.
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http://dx.doi.org/10.1007/s11064-020-03214-9DOI Listing
April 2021

Long-range transport of ozone across the eastern China seas: A case study in coastal cities in southeastern China.

Sci Total Environ 2021 May 7;768:144520. Epub 2021 Jan 7.

Jiangsu Provincial Key Laboratory of Geographic Information Science and Technology, International Institute for Earth System Science, Nanjing University, Nanjing 210023, China; Jiangsu Provincial Academy of Environmental Science, Nanjing 210029, China.

Tropospheric ozone (O) can be transported influenced by large-scale circulation. In this study, an ozone pollution episode in 6 cities of southeastern coastal area of China (SCA) in autumn 2017 was investigated. Compared with the typical local ozone pollution, there was no significant diurnal variations in this pollution episode, the O concentrations maintained a stable level of about 47 ppb continuously. The WRF-CMAQ model as well as the coupled process analysis (PA) and source apportionment modules were used to simulate the formation and transport and quantify the contributions to O. Besides, the HYSPLIT model was used to calculate the backward trajectories arriving in the cities. We find that this pollution was mainly caused by O transport from the eastern China seas (ECS). Under the movement of the Mongolian high-pressure, the O precursors emitted from Beijing-Tianjin-Hebei (BTH), Northeast China (NEC) and Japan-Korea (JK) were transported to ECS then generated O through photochemical reactions. Due to the weak nitrogen oxide titration and the extremely weak ozone deposition on the water surface, O concentrations maintained high during the movement of air masses over ECS and finally affected SCA after long-range transport. The contributions of horizontal advections were significant basically all the day with hourly contribution about 10 ppb hr and extended from surface to 500 m above the ground level. JK contributed the most, with multi-days averaged contribution about 5 ppb and peak up to 30 ppb. The contributions of BTH and NEC were comparable, with average about 2 ppb and hourly peak of 19 and 10 ppb, respectively. For the first time, this study clearly shows that the O precursors emitted from northern China and Japan-Korea contribute to the O pollution in SCA under certain weather conditions, which will help to better understand and predict the O pollution in that area.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144520DOI Listing
May 2021

Impact of weather and emission changes on NO concentrations in China during 2014-2019.

Environ Pollut 2021 Jan 27;269:116163. Epub 2020 Nov 27.

Department of Civil and Environmental Engineering, Hong Kong Polytechnic University, Hong Kong.

Nitrogen dioxide (NO) is one of the most important air pollutants that highly affect the formation of secondary fine particles and tropospheric ozone. In this study based on hourly NO observations from June 2014 to May 2019 and a regional air quality model (WRF-CMAQ), we comprehensively analyzed the spatiotemporal variations of NO concentrations throughout China and in 12 urban agglomerations (UAs) and quantitatively showed the anthropogenic and meteorological factors controlling the interannual variations (IAVs). The ground observations and tropospheric columns show that high NO concentrations are predominantly concentrated in UAs such as Beijing-Tianjin-Hebei (BTH), the Shandong Peninsula (SP), the Central Plain (CP), Central Shaanxi (CS), and the Yangtze River Delta (YRD). For different UAs, the NO IAVs are different. The NO increased first and then decreased in 2016 or 2017 in BTH, YRD, CS, and Cheng-Yu, and decreased from 2014 to 2019 in Harbin-Changchun, CP, SP, Northern Slope of Tianshan Mountain, and Beibu-Gulf, while increased slightly in the Pearl River Delta (PRD) and Hohhot-Baotou-Erdos-Yulin (HBEY). The NO IAVs were primarily dominated by emission changes. The net wintertime decreases of NO in BTH, Yangtze River Middle-Reach, and PRD were mostly contributed by emission reductions from 2014 to 2018, and the significant increase in the wintertime in HBEY was also dominated by emission changes (93%). Weather conditions also have an important effect on the NO IAVS. In BTH and HBEY, the increases of NO in winter of 2016 are mainly attributed to the unfavorable weather conditions and for the significant decreases in the winter of 2017, the favorable weather conditions also play a very important role. This study provides a basic understanding on the current situation of NO pollution and are helpful for policymakers as well as those interested in the study of tropospheric ozone changes in China and downwind areas.
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http://dx.doi.org/10.1016/j.envpol.2020.116163DOI Listing
January 2021

NO Emission Changes Over China During the COVID-19 Epidemic Inferred From Surface NO Observations.

Geophys Res Lett 2020 Oct 2;47(19):e2020GL090080. Epub 2020 Oct 2.

School of Atmospheric Sciences Nanjing University Nanjing China.

The COVID-19 epidemic has substantially limited human activities and affected anthropogenic emissions. In this work, daily NO emissions are inferred using a regional data assimilation system and hourly surface NO measurement over China. The results show that because of the coronavirus outbreak, NO emissions across the whole mainland China dropped sharply after 31 January, began to rise slightly in certain areas after 10 February, and gradually recover across the country after 20 February. Compared with the emissions before the outbreak, NO emissions fell by more than 60% and ~30% in many large cities and most small to medium cities, respectively. Overall, NO emissions were reduced by 36% over China, which were mainly contributed by transportation. Evaluations show that the inverted changes over eastern China are credible, whereas those in western China might be underestimated. These findings are of great significance for exploring the reduction potential of NO emissions in China.
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http://dx.doi.org/10.1029/2020GL090080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537042PMC
October 2020

β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion.

J Exp Med 2020 11;217(11)

Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.

PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti-PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.
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http://dx.doi.org/10.1084/jem.20191115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596815PMC
November 2020

The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis.

Nature 2020 04 8;580(7804):530-535. Epub 2020 Apr 8.

The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China.

Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs. However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.
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http://dx.doi.org/10.1038/s41586-020-2183-2DOI Listing
April 2020

A prospective pilot study of the effect of acupuncture on insulin sensitivity in women with polycystic ovary syndrome and insulin resistance.

Acupunct Med 2020 10 4;38(5):310-318. Epub 2020 Apr 4.

Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Objective: To test the hypothesis that acupuncture improves insulin sensitivity in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR).

Design: Prospective pilot study.

Setting: Guangzhou, China, 2014-2016.

Participants: Eighty women with PCOS aged 18-40 years with body mass index (BMI) above 18.5 kg/m and with homeostatic model assessment for insulin resistance (HOMA-IR) index ⩾2.14.

Interventions: Subjects received acupuncture with combined manual and low-frequency electrical stimulation of the needles three times per week for 6 months.

Primary And Secondary Outcome Measures: The primary outcome was the change in HOMA-IR after 6 months of acupuncture relative to baseline. Secondary outcomes included changes after 6 months of acupuncture and at 3 months of follow-up (both relative to baseline) in oral glucose tolerance test (OGTT) parameters (glucose and insulin levels), anthropometric measurements, and circulating metabolic and endocrine variables.

Results: HOMA-IR and fasting plasma glucose and insulin levels were significantly decreased after 6 months of acupuncture, and both HOMA-IR and fasting insulin remained significantly decreased at 3 months of follow-up. In a subgroup analysis of normal-weight and overweight/obese women, HOMA-IR was reduced after 6 months of acupuncture in both subgroups, but there was no significant difference between the two groups.

Conclusions: Acupuncture treatment in Chinese women with PCOS and IR was associated with an encouraging improvement in insulin sensitivity. Further randomized controlled studies are required to confirm the efficacy of acupuncture for this indication.
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http://dx.doi.org/10.1177/0964528420902144DOI Listing
October 2020

Characterization on gut microbiome of PCOS rats and its further design by shifts in high-fat diet and dihydrotestosterone induction in PCOS rats.

Bioprocess Biosyst Eng 2021 May 10;44(5):953-964. Epub 2020 Mar 10.

School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China.

Polycystic ovary syndrome (PCOS) is associated with gut microbiota disturbance. Emerging evidence has shown that gut microbiota plays a major role in the development of PCOS. To better understand how the gut microbiota contributes to the development of PCOS, we investigated the influences of high-fat diet and hyperandrogenism, independently or synergistically, have on the gut microbiota in rats. Furthermore, we explored the associations between gut microbiota and hyperandrogenism or other hallmarks of PCOS. Twenty female SD rats were randomized at aged 3 weeks into 4 groups (n = 5, each); HA: PCOS rats fed with ordinary diet; HF: rats with high-fat diet (HFD); HA-HF: PCOS rats fed with HFD; and C: control rats with ordinary diet. PCOS rat model was induced by 5α-dihydrotestosterone (DHT) injection for 6 weeks. The fasting blood glucose (FBG), plasma insulin, testosterone, free testosterone, TNF-α, MDA, SOD, LPS, TLR4, TG, TC, HDL-C, and LDL-C levels were measured. The molecular ecology of the fecal gut microbiota was analyzed by 16S rDNA high-throughput sequencing. The results showed that rats in the HA and HA-HF group displayed abnormal estrous cycles with increasing androgen level and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Compare with the C group, relative abundance of the Bacteroidetes phylum decreased significantly in the other groups (P < 0.05). The Chao1 was the highest in the group C and significantly higher than the HA-HF group (P < 0.05). T, FT, insulin, MDA, LPS, and TNF-α levels had the negative correlation with the richness of community (Chao1 index) in the gut. The rats in the HF and HA-HF groups tended to have lower Shannon and Simpson indices than the C group (P < 0.01, respectively). However, there were no significant differences between C group and the HA group in the Shannon and Simpson values. Beta diversity analysis was then performed based on a weighted UniFrac analysis. The PCoA plots showed a clear separation of the C group from the other groups. ANOSIM analysis of variance confirmed that there were statistically significant separations between the C group and the HA, HA-HF, and HF groups (P < 0.01, respectively). These results showed that DHT with HFD could lower diversity of the gut microbial community. Both HFD and DHT could shift the overall gut microbial composition and change the composition of the microbial community in gut. Furthermore, our analyses demonstrated that the levels of TG, MDA, TNF-α, LPS, TLR4, T, FT, FINS, and HDL-C were correlated with the changes of in the gut microbiome. HFD and DHT were associated with the development and pathology of PCOS by shaping gut microbial communities.
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http://dx.doi.org/10.1007/s00449-020-02320-wDOI Listing
May 2021

A multicenter randomized trial of personalized acupuncture, fixed acupuncture, letrozole, and placebo letrozole on live birth in infertile women with polycystic ovary syndrome.

Trials 2020 Mar 4;21(1):239. Epub 2020 Mar 4.

Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing, China.

Background: Traditional Chinese medicine (TCM) usually involves syndrome differentiation and treatment. Acupuncture, one form of TCM, requires the selection of appropriate acupoints and needling techniques, but many clinical trials on acupuncture have used fixed acupuncture protocols without accounting for individual patient differences. We have designed a multicenter randomized controlled trial (RCT) to evaluate whether personalized or fixed acupuncture increases the likelihood of live births in infertile women with polycystic ovary syndrome (PCOS) compared with letrozole or placebo letrozole. We hypothesize that letrozole is more effective than personalized acupuncture, which in turn is more effective than fixed acupuncture, and that placebo letrozole is the least effective intervention. Moreover, we hypothesize that personalized acupuncture is more likely to reduce the miscarriage rate and the risk of pregnancy complications compared with letrozole.

Methods/design: The study is designed as an assessor-blinded RCT. A total of 1100 infertile women with PCOS will be recruited from 28 hospitals and randomly allocated to 4 groups: personalized acupuncture, fixed acupuncture, letrozole, or placebo letrozole. They will receive treatment for 16 weeks, and the primary outcome is live birth. Secondary outcomes include ovulation rate, conception rate, pregnancy rate, pregnancy loss rate, changes in hormonal and metabolic parameters, and changes in quality of life scores. Adverse events will be recorded throughout the trial. All statistical analyses will be performed using IBM SPSS Statistics version 21.0 software (IBM Corp., Armonk, NY, USA), and a P value < 0.05 will be considered statistically significant.

Discussion: This study will be the first multicenter RCT to compare the effect of personalized or fixed acupuncture with letrozole or placebo letrozole on live birth in infertile women with PCOS. The findings will inform whether personalized acupuncture therapy can be considered an alternative treatment to improve the live birth rate in infertile women with PCOS.

Trial Registration: ClinicalTrials.gov, NCT03625531. Registered on July 13, 2018. Chinese Clinical Trial Registry, ChiCTR1800017304. Registered on July 23, 2018.
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http://dx.doi.org/10.1186/s13063-020-4154-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057514PMC
March 2020

Programmable base editing of mutated TERT promoter inhibits brain tumour growth.

Nat Cell Biol 2020 03 17;22(3):282-288. Epub 2020 Feb 17.

Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma. Correction of the -124C>T TERT promoter mutation to -124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.
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http://dx.doi.org/10.1038/s41556-020-0471-6DOI Listing
March 2020

Acute and Subchronic Oral Toxicity Study of Gardenia Yellow E500 in Sprague-Dawley Rats.

Int J Environ Res Public Health 2020 01 14;17(2). Epub 2020 Jan 14.

Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China.

Objective: This study was conducted to evaluate the acute and subchronic toxicity of gardenia yellow, a natural colorant widely used in China and other Asian countries. An acute toxicity test was performed in S-D rats of both genders and the lethal dose (LD) of per oral gardenia yellow was estimated to be more than 15.0 g/kg·bw. In the subchronic study, gardenia yellow was orally administered to rats by gavage at doses of 0, 0.50, 1.50 and 4.50 g/kg·bw/day for 90 days followed by a recovery period of 28 days. No appreciable toxic-related changes were observed in the 0.50 g/kg·bw/day group. When the animals received gardenia yellow at 1.50 g/kg·bw/day or more, body weight loss was observed, and pigments began to deposit in several vital organs, resulting in significant changes of several hematological and biochemical indicators related to the nutritional status of the body, liver and kidney function, more severe in the high dose group. In the recovery period, the alterations of the clinical symptoms and parameters were relieved a lot. Based on the results of the current study, the no observed adverse effect level (NOAEL) of gardenia yellow E500 in rats was set to be 0.50 g/kg·bw/day.
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http://dx.doi.org/10.3390/ijerph17020531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014442PMC
January 2020

KDM3A Senses Oxygen Availability to Regulate PGC-1α-Mediated Mitochondrial Biogenesis.

Mol Cell 2019 12 16;76(6):885-895.e7. Epub 2019 Oct 16.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address:

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.
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http://dx.doi.org/10.1016/j.molcel.2019.09.019DOI Listing
December 2019

PTEN Suppresses Glycolysis by Dephosphorylating and Inhibiting Autophosphorylated PGK1.

Mol Cell 2019 11 3;76(3):516-527.e7. Epub 2019 Sep 3.

Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China. Electronic address:

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis.
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http://dx.doi.org/10.1016/j.molcel.2019.08.006DOI Listing
November 2019

The inflammatory cytokine profile of myelodysplastic syndromes: A meta-analysis.

Medicine (Baltimore) 2019 May;98(22):e15844

Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Background: Accumulating evidence has indicated that the dysregulation of immunological environment has an important role in the pathogenesis of myelodysplastic syndromes (MDS). The previous studies about the levels of the inflammatory cytokines in MDS, such as TNF-α, IFN-γ, IL-6, IL-8, and IL-17, have yielded controversial results. Thus, we performed a meta-analysis to assess the levels of these inflammatory cytokines in MDS.

Methods: A systematic search in PubMed, MEDLINE, Cochrane Library, Web of Science, CNKI, and CBM was conducted to find eligible studies. Meta-analyses were performed using STATA 12.0 for Windows. Heterogeneity between included studies was assessed by I test. We chose SMD as the summary statistic.

Results: A total of 697 individuals from 11 studies were included in this study. Our results suggest the levels of TNF-α, IL-6, IL-8 were significantly higher in MDS patients compared with controls, SMD and 95%CI was 1.48 (0.60, 2.36), 0.71 (0.16, 1.25) and 0.69 (0.28, 1.09), respectively. Moreover, the levels of IL-17 have decreased in the high-risk MDS, the SMD and 95% CI was 2.96 (0.78, 5.15).

Conclusion: A close association between immunological microenvironment disorders and the pathogenesis of MDS was revealed in this meta-analysis. More importantly, the profiles of inflammatory cytokines appear to change along the progression of the disease.
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http://dx.doi.org/10.1097/MD.0000000000015844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708708PMC
May 2019

The protein kinase activity of fructokinase A specifies the antioxidant responses of tumor cells by phosphorylating p62.

Sci Adv 2019 04 24;5(4):eaav4570. Epub 2019 Apr 24.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5'-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62's aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.
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http://dx.doi.org/10.1126/sciadv.aav4570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482012PMC
April 2019

Pharmacological inhibition of EZH2 combined with DNA‑damaging agents interferes with the DNA damage response in MM cells.

Mol Med Rep 2019 May 21;19(5):4249-4255. Epub 2019 Mar 21.

Department of Hematology, People's Liberation Army Center of Hematologic Disorders, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China.

Enhancer of zeste homolog 2 (EZH2) serves a pivotal role in epigenetic silencing by acting as a histone methyltransferase. It has been confirmed that EZH2 overexpression occurs in different types of cancer and is involved in drug resistance, while it remains unclear how a DNA‑damaging event may promote EZH2 expression in multiple myeloma (MM) cells and how EZH2 influences its susceptibility to death in response to DNA‑damaging chemotherapy. The present study examined the impact of EZH2 inhibition on DNA damage‑induced apoptosis in MM cells and elucidated its underlying molecular mechanism. It was demonstrated that pharmacological inhibition of EZH2 sensitized MM cells to DNA‑damaging agents and promoted limited caspase‑dependent apoptosis. Mechanistically, targeting EZH2 with minimal toxic concentrations of a pharmacological inhibitor (GSK126) markedly weakened the accompanying increase in the histone trimethylation H3K27me3 and aggravated DNA damage response (DDR)‑associated apoptosis in vitro. These data preliminarily confirmed the underlying molecular mechanisms of interaction between histone methylation and the DDR in MM cells, forming the rationale for the combination regimen of EZH2 inhibitors with DNA‑damaging agents for the treatment of MM.
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http://dx.doi.org/10.3892/mmr.2019.10075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471932PMC
May 2019

IL-22/IL-22R1 axis is involved in myocardial injury of a mouse cecal ligation and puncture model.

Am J Transl Res 2019 15;11(2):998-1008. Epub 2019 Feb 15.

Medical School of Chinese PLA Beijing, China.

Myocardial depression is a hallmark of severe sepsis, which may result from a complex interplay among several factors. However, the mechanisms are still unclear yet. In this study, we aimed to explore if IL-22/IL-22R1 axis plays a role in the myocardial injury during sepsis. A cecal ligation and puncture (CLP) mouse model was established to explore the histopathological changes and to analyze the role of IL-22/IL-22R1 axis in myocardial injury during the process of sepsis. Histopathologically, myocardial injury was apparently observed with the progress of sepsis but it was improved at 72 h after surgery. On the contrary, the heart tissue in the sham group revealed injury at a limited degree at the first 8 h after surgery and then restored to normal. Results from immunohistochemical study and real-time qPCR showed that IL-22, IL-22R1 and IL-22BP had different changing trends in the progress of sepsis at both protein and mRNA levels. The expression of IL-22R1 and IL-22BP was markedly induced after CLP modeling ( < 0.01), while that of IL-22 was sharply reduced in both groups ( < 0.01). The differences in the expression of IL-22, IL-22R1 and IL-22BP between the sham and CLP groups were significant only at 72 h after surgery ( < 0.05) but not at the other time points ( > 0.05). In conclusion, IL-22/IL-22R1 axis is involved and may have a potential immunoprotective role in the cardiac tissue repair, but the immunoprotection on the cardiac tissue of CLP mice was remarkably damaged in the progress of sepsis and even in the recovery phase.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413265PMC
February 2019

Identification of potential hub-lncRNAs in ischemic stroke based on Subpathway-LNCE method.

J Cell Biochem 2019 08 18;120(8):12832-12842. Epub 2019 Mar 18.

The First Department of Neurology, Weifang People's Hospital, Weifang, Shandong, China.

Ischemic stroke is a devastating condition with a high burden of neurological disability and death. The aim of this study was to explore the potential long noncoding RNA (lncRNA) biomarkers underlying the mechanism of stroke. The Subpathway-LNCE method, which was specifically designed to identify lncRNAs competitively regulated functions in diseases, was applied in ischemic stroke dataset to identify ischemic-stroke-associated dysfunctional subpathway that regulated by lncRNAs. At first, based on the shared microRNA (miRNA) between miRNA-messenger RNA (mRNA) and lncRNA-miRNA interactions, lncRNA-mRNA interactions were constructed. Then, the transcription profiling of 18 631 genes was downloaded from Array Express database and was preprocessed, including normalization and gene expression difference (DEG) analysis, to identify candidate differential pathways using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Next, the pathway-lncRNA-mRNA networks were constructed by linking lncRNAs to candidate differential pathways. At last, there were 11 lncRNAs were identified in the top three subpathways as hub-lncRNAs totally, including LINC00240, LINC00472, LINC00265, LINC00473, MIR497HG, NEXN-AS1, HCG17, MEG8, EPB41L4A-AS1, SNHG7, and BCYRN1, five of which were validated to be very effective stroke biomarker by RT-PCR. In conclusion, we applied Subpathway-LNCE method and experimental verification to identify five lncRNAs, including LINC00265, LINC00473, NEXN-AS1, HCG17, and MEG8, which were considered as important lncRNAs biomarkers in ischemic stroke.
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http://dx.doi.org/10.1002/jcb.28554DOI Listing
August 2019

Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication.

Mol Cell 2018 11 1;72(4):650-660.e8. Epub 2018 Nov 1.

Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Biology Program, MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, The University of TX, Houston, Texas 77030, USA. Electronic address:

DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM phosphorylation binds to an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity in a feedback way. EGFR- and ERK-activated casein kinase 2α (CK2α) phosphorylates nuclear phosphoglycerate kinase (PGK) 1 at S256, resulting in interaction of PGK1 with CDC7. CDC7-bound PGK1 converts ADP to ATP, thereby abrogating the inhibitory effect of ADP on CDC7-ASK activity, promoting the recruitment of DNA helicase to replication origins, DNA replication, cell proliferation, and brain tumorigenesis. These findings reveal an instrumental self-regulatory mechanism of CDC7-ASK activity by its kinase reaction product ADP and a nonglycolytic role for PGK1 in abrogating this negative feedback in promoting tumor development.
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http://dx.doi.org/10.1016/j.molcel.2018.09.007DOI Listing
November 2018

Monoclonal Antibodies versus Histone Deacetylase Inhibitors in Combination with Bortezomib or Lenalidomide plus Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma: An Indirect-Comparison Meta-Analysis of Randomized Controlled Trials.

J Immunol Res 2018 27;2018:7646913. Epub 2018 Jun 27.

Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

During the past decades, agents with novel mechanisms of action, such as monoclonal antibodies (MAbs) and histone deacetylase inhibitors (HDACis) have been applied to treat relapsed or refractory multiple myeloma (RRMM). The treatment outcomes of MAbs versus HDACi in combination with bortezomib or lenalidomide plus dexamethasone remain unknown. We conducted this meta-analysis to compare indirectly the efficacy and safety of MAbs and HDACis in combination with bortezomib or lenalidomide plus dexamethasone. Six trials (eight articles) were included in the meta-analysis with 3270 RRMM patients enrolled. We synthesized hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), risk ratios (RRs) for complete response (CR),very good partial response (VGPR), overall response (OR), progressive disease plus stable disease (PD + SD) and common at least grade 3 adverse events, and their corresponding 95%confidence intervals (95% CI). Treatment with MAbs in combination with bortezomib or lenalidomide plus dexamethasone resulted in longer PFS (HR 0.83, 95% CI: 0.66-0.98), fewer incidences of at least grade 3 thrombocytopenia (RR 0.35, 95% CI: 0.23-0.53), neutropenia (RR 0.70, 95% CI: 0.51-0.96), and sense of fatigue (RR 0.37, 95% CI: 0.17-0.82) than HDACis. The daratumumab plus bortezomib or lenalidomide and dexamethasone might significantly improve PFS in comparison with HDACis plus bortezomib or lenalidomide and dexamethasone (HR 0.55, 95% CI: 0.40-0.74). In conclusion, MAbs may be superior to HDACis in achieving longer PFS and may be better tolerated when in combination therapy with bortezomib or lenalidomide plus dexamethasone.
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http://dx.doi.org/10.1155/2018/7646913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040277PMC
November 2018

EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation.

Mol Cell 2018 04;70(2):197-210.e7

Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; Cancer Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030, USA. Electronic address:

EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation-enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation.
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http://dx.doi.org/10.1016/j.molcel.2018.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114939PMC
April 2018

KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase.

Nature 2017 12 6;552(7684):273-277. Epub 2017 Dec 6.

Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Histone modifications, such as the frequently occurring lysine succinylation, are central to the regulation of chromatin-based processes. However, the mechanism and functional consequences of histone succinylation are unknown. Here we show that the α-ketoglutarate dehydrogenase (α-KGDH) complex is localized in the nucleus in human cell lines and binds to lysine acetyltransferase 2A (KAT2A, also known as GCN5) in the promoter regions of genes. We show that succinyl-coenzyme A (succinyl-CoA) binds to KAT2A. The crystal structure of the catalytic domain of KAT2A in complex with succinyl-CoA at 2.3 Å resolution shows that succinyl-CoA binds to a deep cleft of KAT2A with the succinyl moiety pointing towards the end of a flexible loop 3, which adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Site-directed mutagenesis indicates that tyrosine 645 in this loop has an important role in the selective binding of succinyl-CoA over acetyl-CoA. KAT2A acts as a succinyltransferase and succinylates histone H3 on lysine 79, with a maximum frequency around the transcription start sites of genes. Preventing the α-KGDH complex from entering the nucleus, or expression of KAT2A(Tyr645Ala), reduces gene expression and inhibits tumour cell proliferation and tumour growth. These findings reveal an important mechanism of histone modification and demonstrate that local generation of succinyl-CoA by the nuclear α-KGDH complex coupled with the succinyltransferase activity of KAT2A is instrumental in histone succinylation, tumour cell proliferation, and tumour development.
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http://dx.doi.org/10.1038/nature25003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841452PMC
December 2017

Conversion of PRPS Hexamer to Monomer by AMPK-Mediated Phosphorylation Inhibits Nucleotide Synthesis in Response to Energy Stress.

Cancer Discov 2018 01 26;8(1):94-107. Epub 2017 Oct 26.

Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. Knock-in of nonphosphorylatable PRPS1/2 mutants, which have uninhibited activity, in brain tumor cells under energy stress exhausts cellular ATP and NADPH and increases reactive oxygen species levels, thereby promoting cell apoptosis. The expression of those mutants inhibits brain tumor formation and enhances the inhibitory effect of the glycolysis inhibitor 2-deoxy-d-glucose on tumor growth. Our findings highlight the significance of recalibrating tumor cell metabolism by fine-tuning nucleotide and NAD synthesis in tumor growth. Our findings elucidate an instrumental function of AMPK in direct regulation of nucleic acid and NAD synthesis in tumor cells in response to energy stress. AMPK phosphorylates PRPS1/2, converts PRPS1/2 hexamers to monomers, and inhibits PRPS1/2 activity and subsequent nucleotide and NAD synthesis to maintain tumor cell growth and survival. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760453PMC
January 2018

Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis.

Nat Commun 2017 10 16;8(1):949. Epub 2017 Oct 16.

Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation. AKT binds to and phosphorylates PFKP at S386, and this phosphorylation inhibits the binding of TRIM21 E3 ligase to PFKP and the subsequent TRIM21-mediated polyubiquitylation and degradation of PFKP. PFKP S386 phosphorylation increases PFKP expression and promotes aerobic glycolysis, cell proliferation, and brain tumor growth. In addition, S386 phosphorylation in human glioblastoma specimens positively correlates with PFKP expression, AKT S473 phosphorylation, and poor prognosis. These findings underscore the potential role and regulation of PFKP in human glioblastoma development.Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis. Here the authors show that PFK1 platelet isoform is upregulated in Glioblastoma and is required for tumor growth mechanistically, such upregulation is due to an increased stability induced by AKT activation via phosphorylation on residue S386.
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http://dx.doi.org/10.1038/s41467-017-00906-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643558PMC
October 2017
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