Publications by authors named "Qinong Ye"

87 Publications

miR-1224-3p Promotes Breast Cancer Cell Proliferation and Migration through PGM5-Mediated Aerobic Glycolysis.

J Oncol 2021 19;2021:5529770. Epub 2021 Apr 19.

Medical School of Guizhou University, Guiyang 550025, China.

Metabolic reprogramming of aerobic glycolysis is a hallmark of cancer cells. Regulators of aerobic glycolysis have become targets for cancer diagnosis and therapy. However, the regulators of aerobic glycolysis in breast cancer development have not been well elucidated. Here, we show that the phosphoglucomutase (PGM) family member PGM5 promotes conversion of glucose-1-phosphate (G1P) into glucose-6-phosphate (G6P) and inhibits breast cancer cell proliferation and migration through regulating aerobic glycolysis. In breast cancer patients, PGM5 is significantly downregulated, and its low expression is a predictor of poor prognosis. MicroRNA-1224-3p (miR-1224-3p) inhibits the PGM5 level through directly targeting its 3'-untranslated region and suppresses PGM5-mediated breast cancer cell proliferation, migration, and glycolytic function. Moreover, the miR-1224-3p/PGM5 axis regulates the expression of cell cycle- and apoptosis-related genes and the markers of epithelial-mesenchymal transition (EMT), a process involved in migration and metastasis of cancer cells. Taken together, our results indicate that miR-1224-3p/PGM5 axis plays important roles in breast cancer cell proliferation, migration, and aerobic glycolysis and may be a potential target for breast cancer therapy.
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http://dx.doi.org/10.1155/2021/5529770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079189PMC
April 2021

Nonradioactive direct telomerase activity detection using biotin-labeled primers.

J Clin Lab Anal 2021 May 7:e23800. Epub 2021 May 7.

Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China.

Background: Telomerase is a ribonucleoprotein enzyme responsible for maintenance of telomere length which expressed in more than 85% of cancer cells but undetectable in most normal tissue cells. Therefore, telomerase serves as a diagnostic marker of cancers. Two commonly used telomerase activity detection methods, the telomerase repeated amplification protocol (TRAP) and the direct telomerase assay (DTA), have disadvantages that mainly arise from reliance on PCR amplification or the use of an isotope. A safe, low-cost and reliable telomerase activity detection method is still lacking.

Method: We modified DTA method using biotin-labeled primers (Biotin-DTA) and optimized the method by adjusting cell culture temperature and KCl concentration. The sensitivity of the method was confirmed to detect endogenous telomerase activity. The reliability was verified by detection of telomerase activity of published telomerase regulators. The stability was confirmed by comparing the method with TRAP method.

Results: Cells cultured in 32°C and KCl concentration at 200 mM or 250 mM resulted in robust Biotin-DTA signal. Endogenous telomerase activity can be detected, which suggested an similar sensitivity as DTA using radioactive isotope markers. Knockdown of telomerase assembly regulator PES1 and DKC1 efficiently reduced telomerase activity. Compared with TRAP method, Biotin-DTA assay offers greater signal stability over a range of analyte protein amounts.

Conclusion: Biotin-labeled, PCR-free, and nonradioactive direct telomerase assay is a promising new method for the easy, low-cost, and quantitative detection of telomerase activity.
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http://dx.doi.org/10.1002/jcla.23800DOI Listing
May 2021

-Mediated Regulation of mA-Modified by mA Reader IGF2BP3 Drives ccRCC Progression.

Cancer Res 2021 02 8;81(4):923-934. Epub 2020 Dec 8.

CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China.

Aberrant -methyladenosine (mA) modification has emerged as a driver of tumor initiation and progression, yet how long noncoding RNAs (lncRNA) are involved in the regulation of mA remains unknown. Here we utilize data from 12 cancer types from The Cancer Genome Atlas to comprehensively map lncRNAs that are potentially deregulated by DNA methylation. A novel DNA methylation-deregulated and RNA mA reader-cooperating lncRNA () facilitated tumor growth and metastasis in clear cell renal cell carcinoma (ccRCC). Mechanistically, bound insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) to stabilize target genes, including the cell-cycle kinase and three extracellular matrix components (, and ), by specifically enhancing IGF2BP3 activity on them in an mA-dependent manner. Consequently, and IGF2BP3 enhanced the G-S transition, thus promoting cell proliferation in ccRCC. In patients with ccRCC, high coexpression of and IGF2BP3 was associated with poor outcomes. Our findings reveal that cooperates with IGF2BP3 to regulate target genes in an mA-dependent manner and may represent a potential diagnostic, prognostic, and therapeutic target in ccRCC. SIGNIFICANCE: This study demonstrates that the lncRNA acts as a cofactor for IGF2BP3 to stabilize target genes in an mA-dependent manner, thus exerting essential oncogenic roles in ccRCC.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1619DOI Listing
February 2021

The ubiquitin ligase E6AP facilitates HDAC6-mediated deacetylation and degradation of tumor suppressors.

Signal Transduct Target Ther 2020 10 19;5(1):243. Epub 2020 Oct 19.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, 100850, PR China.

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http://dx.doi.org/10.1038/s41392-020-00330-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573597PMC
October 2020

Metabolism and immunity in breast cancer.

Front Med 2021 Apr 19;15(2):178-207. Epub 2020 Oct 19.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.

Breast cancer is one of the most common malignancies that seriously threaten women's health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host's immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.
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http://dx.doi.org/10.1007/s11684-020-0793-6DOI Listing
April 2021

Oleate acid-stimulated HMMR expression by CEBPα is associated with nonalcoholic steatohepatitis and hepatocellular carcinoma.

Int J Biol Sci 2020 27;16(15):2812-2827. Epub 2020 Aug 27.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.

Non-alcoholic steatohepatitis (NASH) is a type of nonalcoholic fatty liver disease and has become a major risk factor for hepatocellular carcinoma (HCC). However, the underlying pathophysiological mechanisms are still elusive. Here, we identify hyaluronan-mediated motility receptor (HMMR) as a critical gene associated with NASH/HCC by combination of bioinformatic analysis and functional experiments. Analysis of differentially expressed genes (DEGs) between normal controls and NASH/HCC identified 5 hub genes (HMMR, UBE2T, TYMS, PTTG1 and GINS2). Based on the common DEGs, analyses of univariate and multivariate Cox regression and the area under the curve (AUC) value of the receiver operating characteristic (ROC) indicate that HMMR is the most significant gene associated with NASH/HCC among five hub genes. Oleate acid (OA), one of fatty acids that induce cellular adipogenesis, stimulates HMMR expression via CCAAT/enhancer-binding protein α (CEBPα). CEBPα increases the expression of HMMR through binding to its promoter. HMMR promotes HCC cell proliferation via activation of G1/S and G2/M checkpoint transitions, concomitant with a marked increase of the positive cell cycle regulators, including cyclin D1, cyclin E, and cyclin B1. Knockdown of HMMR suppresses HCC tumor growth in nude mice. Our study identifies an important role of HMMR in NASH/HCC, and suggests that HMMR may be a useful target for therapy and prognostic prediction of NASH/HCC patients.
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http://dx.doi.org/10.7150/ijbs.49785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545721PMC
August 2020

Let-7a-5p inhibits triple-negative breast tumor growth and metastasis through GLUT12-mediated warburg effect.

Cancer Lett 2020 12 15;495:53-65. Epub 2020 Sep 15.

Medical School of Guizhou University, Guiyang, 550025, China; Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China. Electronic address:

Triple-negative breast cancer (TNBC) is known for its aggressive phenotype with limited treatment modalities and poor prognosis. The Warburg effect (aerobic glycolysis) is a hallmark of cancer that serves as a promising target for diagnosis and therapy. However, how aerobic glycolysis regulates TNBC remains largely unknown. Here, we show that the glucose transporter (GLUT) family member GLUT12 promotes TNBC tumor growth and metastasis in vitro and in vivo through regulating aerobic glycolysis. MicroRNA let-7a-5p, a tumor suppressor, inhibited GLUT12 expression by targeting its 3'-untranslated region, and suppressed GLUT12-mediated TNBC tumor growth, metastasis, and glycolytic function, including alterations of glucose uptake, lactate production, ATP generation, extracellular acidification rate, and oxygen consumption rate. Inhibiting aerobic glycolysis abolished the ability of let-7a-5p and GLUT12 to regulate TNBC cell proliferation, migration and invasion. In TNBC patients, GLUT12 was significantly upregulated, and let-7a-5p expression was inversely correlated with GLUT12 expression. High expression of let-7a-5p and GLUT12 predicted better and worse clinical outcomes, respectively. Taken together, our results indicate that the let-7a-5p/GLUT12 axis plays key roles in TNBC tumor growth and metastasis, and aerobic glycolysis, and is a potential target for TNBC treatment.
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http://dx.doi.org/10.1016/j.canlet.2020.09.012DOI Listing
December 2020

Snail promotes the generation of vascular endothelium by breast cancer cells.

Cell Death Dis 2020 06 15;11(6):457. Epub 2020 Jun 15.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, 100850, Beijing, China.

A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial-mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.
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http://dx.doi.org/10.1038/s41419-020-2651-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295784PMC
June 2020

Long noncoding RNA MYLK-AS1 promotes growth and invasion of hepatocellular carcinoma through the EGFR/HER2-ERK1/2 signaling pathway.

Int J Biol Sci 2020 27;16(11):1989-2000. Epub 2020 Apr 27.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China.

The epidermal growth factor receptor (EGFR) family members EGFR and HER2 play pivotal roles in oncogenesis and tumor progression. Anticancer drugs targeting EGFR and HER2 have been developed. Long noncoding RNAs (lncRNAs) have been reported to regulate cancer development and progression through signaling pathways. However, lncRNAs that regulate EGFR and HER2 expression remain unknown. Here, we show that lncRNA myosin light chain kinase-antisense RNA 1 (MYLK-AS1) promotes EGFR and HER2 expression and activates their downstream signaling pathway. MYLK-AS1 increases hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion . Consistently, MYLK-AS1 knockdown hinders tumor growth . Mechanistically, MYLK-AS1 enhances HCC cell proliferation, migration, and invasion through stimulating the EGFR/HER2-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In addition, MYLK-AS1 is overexpressed in HCC patients and negatively correlated with HCC prognosis. Thus, MYLK-AS1 is an upstream regulator of EGFR/HER2, and acts as an oncogene, suggesting an additional target for cancer therapeutics.
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http://dx.doi.org/10.7150/ijbs.43062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211179PMC
April 2020

miR-489-3p/SIX1 Axis Regulates Melanoma Proliferation and Glycolytic Potential.

Mol Ther Oncolytics 2020 Mar 27;16:30-40. Epub 2019 Nov 27.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, No. 27 Taiping Road, Beijing 100850, China.

Sine oculis homeobox 1 (SIX1), a key transcription factor for regulating aerobic glycolysis, participates in the occurrence of various cancer types. However, the role of SIX1 in melanoma and the upstream regulating mechanisms of SIX1 remain to be further investigated. MicroRNAs (miRNAs) have emerged as key regulators in tumorigenesis and progression. Here, we show that miR-489-3p suppresses SIX1 expression by directly targeting its 3' untranslated region (3' UTR) in melanoma cells. miR-489-3p suppressed melanoma cell proliferation, migration, and invasion through inhibition of SIX1. Mechanistically, by targeting SIX1, miR-489-3p dampens glycolysis, with decreased glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), as well as an increased oxygen consumption rate (OCR). Importantly, glycolysis regulated by the miR-489-3p/SIX1 axis is critical for its regulation of melanoma growth and metastasis both and . In melanoma patients, miR-489-3p expression is negatively correlated with SIX1 expression. In addition, patients who had increased glucose uptake in tumors and with metastasis assessed by positron emission tomography (PET) scans showed decreased miR-489-3p expression and increased expression of SIX1. Collectively, our study demonstrates the importance of the miR-489-3p/SIX1 axis in melanoma, which can be a potential and a promising therapeutic target in melanoma.
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http://dx.doi.org/10.1016/j.omto.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109510PMC
March 2020

Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy.

Proc Natl Acad Sci U S A 2020 03 11;117(12):6640-6650. Epub 2020 Mar 11.

Chinese Academy of Sciences (CAS) Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163 Suzhou, China;

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.
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http://dx.doi.org/10.1073/pnas.1921445117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104341PMC
March 2020

PES1 is a critical component of telomerase assembly and regulates cellular senescence.

Sci Adv 2019 05 15;5(5):eaav1090. Epub 2019 May 15.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.

Telomerase defers the onset of telomere shortening and cellular senescence by adding telomeric repeat DNA to chromosome ends, and its activation contributes to carcinogenesis. Telomerase minimally consists of the telomerase reverse transcriptase (TERT) and the telomerase RNA (TR). However, how telomerase assembles is largely unknown. Here, we demonstrate that PES1 (Pescadillo), a protein overexpressed in many cancers, forms a complex with TERT and TR through direct interaction with TERT, regulating telomerase activity, telomere length maintenance, and senescence. PES1 does not interact with the previously reported telomerase components Reptin, Pontin, p23, and Hsp90. PES1 facilitates telomerase assembly by promoting direct interaction between TERT and TR without affecting TERT and TR levels. PES1 expression correlates positively with telomerase activity and negatively with senescence in patients with breast cancer. Thus, we identify a previously unknown telomerase complex, and targeting PES1 may open a new avenue for cancer therapy.
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http://dx.doi.org/10.1126/sciadv.aav1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520020PMC
May 2019

GATA1 Promotes Gemcitabine Resistance in Pancreatic Cancer through Antiapoptotic Pathway.

J Oncol 2019 10;2019:9474273. Epub 2019 Apr 10.

Department of Hepatobiliary and Pancreatic Surgical Oncology, Medical School of Chinese People's Liberation Army, Beijing 100853, China.

Gemcitabine-based chemotherapy is the first-line treatment for pancreatic cancer. However, chemoresistance is a major obstacle to drug efficacy, leading to poor prognosis. Little progress has been achieved although multiple mechanisms are investigated. Therefore, effective strategies are urgently needed to overcome drug resistance. Here, we demonstrate that the transcription factor GATA binding protein 1 (GATA1) promotes gemcitabine resistance in pancreatic cancer through antiapoptotic pathway. GATA1 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) tissues, and GATA1 status is an independent predictor of prognosis and response to gemcitabine therapy. Further investigation demonstrates GATA1 is involved in both intrinsic and acquired gemcitabine resistance in PDAC cells. Mechanistically, we find that GATA1 upregulates Bcl-XL expression by binding to its promoter and thus induces gemcitabine resistance through enhancing Bcl-XL mediated antiapoptosis in and in . Moreover, in PDAC patients, Bcl-XL expression is positively correlated with GATA1 level and predicts clinical outcomes and gemcitabine response. Taken together, our results indicate that GATA1 is a novel marker and potential target for pancreatic cancer. Targeting GATA1 combined with Bcl-XL may be a promising strategy to enhance gemcitabine response.
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http://dx.doi.org/10.1155/2019/9474273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481023PMC
April 2019

Cholesterol Induces Epithelial-to-Mesenchymal Transition of Prostate Cancer Cells by Suppressing Degradation of EGFR through APMAP.

Cancer Res 2019 06 15;79(12):3063-3075. Epub 2019 Apr 15.

CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China.

Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. SIGNIFICANCE: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3063/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3295DOI Listing
June 2019

Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis.

Nat Commun 2019 01 18;10(1):313. Epub 2019 Jan 18.

Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, 100853, Beijing, China.

Osteoarthritis (OA) has been recognized as the most common chronic age-related disease. Cartilage degeneration influences OA therapy. Here we report that hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is essential for OA development. Elevated HPIP levels are found in OA patients. Col2a1-CreER/HPIP mice exhibit obvious skeletal abnormalities compared with their HPIP littermates. HPIP deficiency in mice protects against developing OA. Moreover, intra-articular injection of adeno-associated virus carrying HPIP-specific short hairpin RNA in vivo attenuates OA histological signs. Notably, in vitro RNA-sequencing and chromatin immunoprecipitation sequencing profiles identify that HPIP modulates OA cartilage degeneration through transcriptional activation of Wnt target genes. Mechanistically, HPIP promotes the transcription of Wnt targets by interacting with lymphoid enhancer binding factor 1 (LEF1). Furthermore, HPIP potentiates the transcriptional activity of LEF1 and acetylates histone H3 lysine 56 in the promoters of Wnt targets, suggesting that HPIP is an attractive target in OA regulatory network.
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http://dx.doi.org/10.1038/s41467-018-08277-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338798PMC
January 2019

The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer.

Oncogene 2019 03 23;38(13):2291-2304. Epub 2018 Nov 23.

Department of Oncology, PLA General Hospital, Beijing, China.

Epidermal growth factor receptor (EGFR) status is the major determinant of non-small cell lung cancer (NSCLC) therapy selection. Studies have hinted that EGFR antibodies or tyrosine kinase inhibitors were beneficial in patients with EGFR mutation-negative but EGFR-overexpressing of NSCLC. However, the mechanisms underlying EGFR amplification and overexpression in NSCLC remain largely unknown. Here, we report that rs884225, a single nucleotide polymorphism in the EGFR 3'-terminal untranslated region, was significantly associated with EGFR expression level and contributed to NSCLC susceptibility. Mechanistically, the rs884225 C allele enhanced EGFR expression by altering the miR-103a-3p binding site, thus impairing miR-103a-3p's anti-tumourigenic function. As a tumour suppressor gene, miR-103a-3p expression correlated with overall and recurrence-free survival in NSCLC patients. Furthermore, miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in EGFR wild-type NSCLC cell lines, respectively, which substantially reduced EGFR expression and activity. Thus, rs884225 may be a biomarker for NSCLC susceptibility, and miR-103a-3p may be a potential therapeutic target in NSCLC.
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http://dx.doi.org/10.1038/s41388-018-0576-6DOI Listing
March 2019

Aminophenols increase proliferation of thyroid tumor cells by inducing the transcription factor activity of estrogen receptor α.

Biomed Pharmacother 2019 Jan 3;109:621-628. Epub 2018 Nov 3.

Department of Endocrinology, Chinese PLA General Hospital, Medical College of Chinese PLA, Beijing, 100853, PR China. Electronic address:

Aminophenols, which are widely used as components of hair dye and medicine, may function as environmental endocrine disruptors by regulating the proliferation of endocrine-related cancers. Estrogen receptor α (ERα) is a key regulator of breast cancer. Recently, it was found that ERα may also participate in the transformation and progression of thyroid tumors, but its interaction with aminophenols and its function in thyroid tumors is not clear. In this study, the transcription factor activity of ERα in BHP10-3 cells (a thyroid tumor cell line) was examined using luciferase assays. The promoter recruitment of ERα was examined using chromatin co-precipitation (ChIP). Additionally, in an in vivo study, BHP10-3 cells were transplanted into nude mice. Upon administration of aminophenols, the transcription factor activity of ERα was significantly increased in BHP10-3 cells, and the recruitment of ERα to the promoter of its target gene was increased. Aminophenols enhanced the in vitro and in vivo proliferation of BHP10-3 cells. By discovering that aminophenols induce the onco-promoting activity of ERα, our study extends the understanding of the function of aminophenols and suggests that ERα is a potential therapeutic target for the treatment of thyroid tumors.
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http://dx.doi.org/10.1016/j.biopha.2018.10.168DOI Listing
January 2019

[Expression, purification and binding activity analysis of von Hippel-Lindau (VHL)].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2018 Jun;34(6):535-540

Department of Hematology, General Hospital of PLA Rocket Force, Beijing 100088, China. *Corresponding authors, E-mail:

Objective To purify recombinant protein of human von Hippel-Lindau (VHL) and identify its function. Methods VHL gene sequence was amplified from human mammary cDNA using PCR and inserted into the prokaryotic expression vector pGEX-KG. Glutathione S-transferase-VHL (GST-VHL) recombinant plasmid we obtained was converted into BL21(DE3) sensitive bacteria to induce a small amount of GST-VHL protein. The expressed product was detected by SDS-PAGE and Western blot analysis. The recombinant protein was purified by GST beads and its function was verified by GST pull-down assay. Results The obtained recombinant plasmid could be successfully digested by double enzymes. Gene sequencing showed that the VHL sequence was correct and there was no mutation. The recombinant protein with approximately relative molecular mass (M) 56 000 was purified by converting recombinant plasmid to BL21(DE3) sensitive bacteria and inducing it in small quantities. GST pull-down assay verified that GST-VHL recombinant protein had the function of binding hypoxia inducible factor-1 α (HIF-1 α) in vitro. Conclusion GST-VHL recombinant protein is purified and can combine with HIF-1α protein in vitro.
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June 2018

Association Analysis between Body Mass Index and Genomic DNA Methylation across 15 Major Cancer Types.

J Cancer 2018 22;9(14):2532-2542. Epub 2018 Jun 22.

CAS Key Laboratory of Bio-medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou 215163, China.

Cancer incidence and mortality increase with increasing body mass index (BMI), but BMI-associated epigenetic alterations in cancer remain elusive. We hypothesized that BMI would be associated with DNA methylation alterations in cancers. To test this hypothesis, here, we estimated the associations between DNA methylation and BMI through two different methods across 15 cancer types, at approximately 485,000 CpG sites and 2415 samples using data from The Cancer Genome Atlas. After comparing the DNA methylation levels in control BMI and high BMI individuals, we found differentially methylated CpG sites (DMSs) in cholangiocarcinoma (CHOL), colon adenocarcinoma (COAD), and uterine corpus endometrial carcinoma (UCEC) ( < 0.05). The DMSs of COAD or UCEC were enriched in several obesity-induced and cancer-related pathways. Next, when BMI was used as a continuous variable, we identified BMI-associated methylated CpG sites (BMS) ( () < 0.05) in CHOL (BMS = 1), COAD (BMS = 1), and UCEC (BMS = 4) using multivariable linear regression. In UCEC, three of the BMSs can predict the clinical outcomes and survival of patients with the tumors. Overall, we observed associations between DNA methylation and high BMI in CHOL, COAD, and UCEC. Furthermore, three BMI-associated CpGs were identified as potential biomarkers for UCEC prognosis.
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http://dx.doi.org/10.7150/jca.23535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036895PMC
June 2018

Transcriptional Regulation of the Warburg Effect in Cancer by SIX1.

Cancer Cell 2018 03 15;33(3):368-385.e7. Epub 2018 Feb 15.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China. Electronic address:

Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.
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http://dx.doi.org/10.1016/j.ccell.2018.01.010DOI Listing
March 2018

Src-mediated phosphorylation converts FHL1 from tumor suppressor to tumor promoter.

J Cell Biol 2018 04 6;217(4):1335-1351. Epub 2018 Feb 6.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Human Anatomy, Histology and Embryology, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China

FHL1 has been recognized for a long time as a tumor suppressor protein that associates with both the actin cytoskeleton and the transcriptional machinery. We present in this study a paradigm that phosphorylated FHL1 functions as an oncogenic protein by promoting tumor cell proliferation. The cytosolic tyrosine kinase Src interacts with and phosphorylates FHL1 at Y149 and Y272, which switches FHL1 from a tumor suppressor to a cell growth accelerator. Phosphorylated FHL1 translocates into the nucleus, where it binds to the transcription factor BCLAF1 and promotes tumor cell growth. Importantly, the phosphorylation of FHL1 is increased in tissues from lung adenocarcinoma patients despite the down-regulation of total FHL1 expression. Kindlin-2 was found to interact with FHL1 and recruit FHL1 to focal adhesions. Kindlin-2 competes with Src for binding to FHL1 and suppresses Src-mediated FHL1 phosphorylation. Collectively, we demonstrate that FHL1 can either suppress or promote tumor cell growth depending on the status of the sites for phosphorylation by Src.
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http://dx.doi.org/10.1083/jcb.201708064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881501PMC
April 2018

Biological effects of adipocytes in sulfur mustard induced toxicity.

Toxicology 2018 01 10;393:140-149. Epub 2017 Nov 10.

State Key Laboratory of Toxicology and Medical Countermeasures, and Laboratory of Toxicant Analysis, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China. Electronic address:

Sulphur mustard (2,2'-dichloroethyl sulfide; SM) is a vesicant chemical warfare agent whose mechanism of acute or chronic action is not known with any certainty and to date there is no effective antidote. SM accumulation in adipose tissue (AT) has been originally verified in our previous study. To evaluate the biological effect caused by the presence of abundant SM in adipocyte and assess the biological role of AT in SM poisoning, in vitro and in vivo experiments were performed. High content analysis revealed multi-cytotoxicity in SM exposed cells in a time and dose dependent manner, and adipocytes showed a relative moderate damage compared with non-adipocytes. Cell co-culture model was established and revealed the adverse effect of SM-exposed adipocyte supernatant on the growth of co-cultured cells. The pathological changes in AT from 10mg/kg SM percutaneously exposed rats were checked and inflammation phenomena were observed. The mRNA and protein levels of inflammation-related adipokines secreted from AT in rats exposed to 1, 3 and 10mg/kg doses of SM were determined by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assays. The expressions of proinflammatory and anti-inflammatory adipokines together promoted the inflammation development in the body. The positive correlations between AT and serum adipokine levels were explored, which demonstrated a substantial role of AT in systemic inflammation responding to SM exposure. Thus, AT is not only a target of SM but also a modulator in the SM toxicity.
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http://dx.doi.org/10.1016/j.tox.2017.11.011DOI Listing
January 2018

miR-216a inhibits osteosarcoma cell proliferation, invasion and metastasis by targeting CDK14.

Cell Death Dis 2017 10 12;8(10):e3103. Epub 2017 Oct 12.

Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, China.

Osteosarcoma (OS) has emerged as the most common primary musculoskeletal malignant tumour affecting children and young adults. Cyclin-dependent kinases (CDKs) are closely associated with gene regulation in tumour biology. Accumulating evidence indicates that the aberrant function of CDK14 is involved in a broad spectrum of diseases and is associated with clinical outcomes. MicroRNAs (miRNAs) are crucial epigenetic regulators in the development of OS. However, the essential role of CDK14 and the molecular mechanisms by which miRNAs regulate CDK14 in the oncogenesis and progression of OS have not been fully elucidated. Here we found that CDK14 expression was closely associated with poor prognosis and overall survival of OS patients. Using dual-luciferase reporter assays, we also found that miR-216a inhibits CDK14 expression by binding to the 3'-untranslated region of CDK14. Overexpression of miR-216a significantly suppressed cell proliferation, migration and invasion in vivo and in vitro by inhibiting CDK14 production. Overexpression of CDK14 in the miR-216a-transfected OS cells effectively rescued the suppression of cell proliferation, migration and invasion caused by miR-216a. In addition, Kaplan-Meier analysis indicated that miR-216a expression predicted favourable clinical outcomes for OS patients. Moreover, miR-216a expression was downregulated in OS patients and was negatively associated with CDK14 expression. Overall, these data highlight the role of the miR-216a/CDK14 axis as a novel pleiotropic modulator and demonstrate the associated molecular mechanisms, thus suggesting the intriguing possibility that miR-216a activation and CDK14 inhibition may be novel and attractive therapeutic strategies for treating OS patients.
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http://dx.doi.org/10.1038/cddis.2017.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682665PMC
October 2017

The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis.

Cell Death Dis 2017 07 13;8(7):e2928. Epub 2017 Jul 13.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.

Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3'-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer.
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http://dx.doi.org/10.1038/cddis.2017.325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550870PMC
July 2017

miR-30a-5p enhances paclitaxel sensitivity in non-small cell lung cancer through targeting BCL-2 expression.

J Mol Med (Berl) 2017 08 9;95(8):861-871. Epub 2017 May 9.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China.

Lung cancer remains the leading cause of cancer-related death worldwide. Paclitaxel, either as monotherapy or combined with other agents, is the standard treatment for advanced non-small cell lung cancer (NSCLC), the most common type of lung cancer. However, both de novo and acquired resistance against paclitaxel frequently occurs and represents a huge clinical problem. The underlying mechanisms remain poorly characterized. Here, by comparing microRNA (miRNA) expression levels using miRNA arrays, we observed differential expression of miR-30a-5p in two independent lung cancer cell pairs (paclitaxel-resistant vs paclitaxel-sensitive A549 cell lines). Overexpression of miR-30a-5p sensitizes NSCLC cells to paclitaxel both in vitro and in vivo. In addition, miR-30a-5p increases paclitaxel sensitivity by promoting chemotherapy-induced apoptosis via downregulating BCL-2, a key apoptosis regulator. High miR-30a-5p expression is positively correlated with enhanced responsiveness to paclitaxel and predicts a more favorable clinical outcome in NSCLC patients. Moreover, miR-30a-5p expression is negatively correlated with BCL-2 expression in NSCLC tissues. These data indicate that miR-30a-5p may be useful to treat paclitaxel-resistant lung cancer and may also provide a biomarker to predict paclitaxel responsiveness in lung cancer.

Key Messages: BCL-2 is a novel direct target of miR-30a-5p. miR-30a-5p enhances NSCLC paclitaxel sensitivity in vitro and in vivo. miR-30a-5p sensitizes NSCLC cells to paclitaxel by inducing apoptosis through BCL-2 inhibition. miR-30a-5p negatively correlates with BCL-2 and predicts a favorable clinical outcome in NSCLC patients.
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http://dx.doi.org/10.1007/s00109-017-1539-zDOI Listing
August 2017

miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect.

Cancer Lett 2017 08 29;400:89-98. Epub 2017 Apr 29.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, China. Electronic address:

Lactate dehydrogenase A (LDHA), a key enzyme regulating aerobic glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including LDHA, are being developed. However, the mechanisms of LDHA inhibition and the physiological significance of the LDHA inhibitors in cancer cells are unclear. Here, we show that microRNA-30a-5p (miR-30a-5p) suppresses LDHA expression by directly targeting its 3'-UTR. Through inhibition of LDHA, miR-30a-5p dampens glycolysis by decreasing glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in breast cancer cells. Importantly, glycolysis regulated by miR-30a-5p is critical for its regulating breast tumor growth and metastasis both in vitro and in vivo. In breast cancer patients, miR-30a-5p expression is negatively correlated with LDHA expression. Moreover, patients who had increased glucose uptake in tumors assessed by PET scans showed decreased miR-30a-5p expression and increased expression of LDHA. Our findings provide clues regarding the role of miR-30a-5p as a tumor suppressor in breast cancer through the inhibition of LDHA. Targeting LDHA through miR-30a-5p could be a potential therapeutic strategy in breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2017.04.034DOI Listing
August 2017

A signature motif in LIM proteins mediates binding to checkpoint proteins and increases tumour radiosensitivity.

Nat Commun 2017 01 17;8:14059. Epub 2017 Jan 17.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.

Tumour radiotherapy resistance involves the cell cycle pathway. CDC25 phosphatases are key cell cycle regulators. However, how CDC25 activity is precisely controlled remains largely unknown. Here, we show that LIM domain-containing proteins, such as FHL1, increase inhibitory CDC25 phosphorylation by forming a complex with CHK2 and CDC25, and sequester CDC25 in the cytoplasm by forming another complex with 14-3-3 and CDC25, resulting in increased radioresistance in cancer cells. FHL1 expression, induced by ionizing irradiation in a SP1- and MLL1-dependent manner, positively correlates with radioresistance in cancer patients. We identify a cell-penetrating 11 amino-acid motif within LIM domains (eLIM) that is sufficient for binding CHK2 and CDC25, reducing the CHK2-CDC25 and CDC25-14-3-3 interaction and enhancing CDC25 activity and cancer radiosensitivity accompanied by mitotic catastrophe and apoptosis. Our results provide novel insight into molecular mechanisms underlying CDC25 activity regulation. LIM protein inhibition or use of eLIM may be new strategies for improving tumour radiosensitivity.
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http://dx.doi.org/10.1038/ncomms14059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247581PMC
January 2017

MiR-495 functions as an adjuvant to radiation therapy by reducing the radiation-induced bystander effect.

Acta Biochim Biophys Sin (Shanghai) 2016 Nov 3;48(11):1026-1033. Epub 2016 Oct 3.

Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China

The radiation-induced bystander effect (RIBE) is an important factor in tumor radiation therapy because it may increase the probability of normal cellular injury and the likelihood of secondary cancers after radiotherapy. Here, we identified the role of miR-495 in alleviating RIBEs during radiotherapy. Luciferase reporter assay results confirmed that miR-495 regulated endothelial nitric oxide synthase (eNOS) by targeting the Sp1 3'-untranslated region. Consequently, after radiation, tumor cells expressed less eNOS and Sp1 than controls. In vitro cell irradiation data based on flow-cytometric analysis and enzymed linked immunosorbent assay confirmed that nitric oxide (NO) and its downstream product transforming growth factor β1 (TGF-β1) were critical signaling factors contributing to RIBEs. Fewer normal LO liver cells were injured and fewer micronuclei were observed when treated with the medium of the miR-495 overexpressing HepG2 and ZR75-1 tumor cells. Accordingly, treatment with the miR-495 antagomir led to higher NO and TGF-β1 levels and more injured LO cells. In vivo experiments indicated that local irradiation of tumors overexpressing miR-495 produced fewer necrotic foci in non-irradiated liver tissue compared with controls. miR-495 was upregulated in clinical cancer tissues compared with adjacent non-cancerous tissues, and radiation significantly reduced the expression level of miR-495 in carcinoma cell lines. In summary, miR-495 may have promise as an adjuvant for tumor radiation therapy to decrease RIBEs involving the Sp1/eNOS pathway.
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http://dx.doi.org/10.1093/abbs/gmw098DOI Listing
November 2016

Transcription factor activity of estrogen receptor α activation upon nonylphenol or bisphenol A treatment enhances the in vitro proliferation, invasion, and migration of neuroblastoma cells.

Onco Targets Ther 2016 13;9:3451-63. Epub 2016 Jun 13.

Department of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, People's Republic of China.

Many kinds of endocrine-disrupting chemicals (EDCs), for example, the environmental estrogens bisphenol A and nonylphenol, may regulate the activity of estrogen receptor α (ERα) and therefore induce potential disruption of normal endocrine function. However, the involvement of EDCs in human cancers, especially in endocrine-related cancer neuroblastoma regulation, is not very clear. In this work, results showed that upon bisphenol A or nonylphenol treatment, the transcription factor activity of ERα was significantly increased in neuroblastoma cell line SH-SY5Y. Bisphenol A and nonylphenol could enhance ERα activity via recruiting it to the target gene promoter. Furthermore, treatment of bisphenol A and nonylphenol enhanced the in vitro proliferation, invasion, and migration ability of neuroblastoma cells. By investigating the role of EDC-induced ERα upregulation, our data extend the understanding of the function of EDCs and further suggest that ERα might be a potential therapeutic target in human neuroblastoma treatment.
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http://dx.doi.org/10.2147/OTT.S105745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913548PMC
July 2016

Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer.

Oncotarget 2016 Jul;7(27):42585-42597

Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.
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http://dx.doi.org/10.18632/oncotarget.10018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173158PMC
July 2016