Publications by authors named "Hongchang Li"

73 Publications

Polyphyllin D induces apoptosis and protective autophagy in breast cancer cells through JNK1-Bcl-2 pathway.

J Ethnopharmacol 2021 Sep 2;282:114591. Epub 2021 Sep 2.

Department of General Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address:

Ethnopharmacological Relevance: Polyphyllin D (PD), an active component from rhizome of Paris polyphylla Sm, root and rhizome, shows a strong anti-cancer activity in several cancers. However, whether autophagy is involved in PD-induced cell death in breast cancer cells and its molecular mechanism has not yet been elucidated.

Aim Of The Study: To explore the anti-tumor effects of PD in breast cancer and the underlying mechanisms.

Materials And Methods: PD was isolated from P. polyphylla Sm and confirmed by HPLC and NMR. The role of PD in cell viability, apoptosis, autophagy in breast cancer cells were determined.

Results: PD shows significant anti-tumor activity by inhibit cell proliferation and induce caspase-dependent apoptosis in breast cancer cells. Moreover, PD treatment could induce autophagy by activation of JNK1/Bcl-2 pathway. Importantly, blocking of autophagy by using autophagy inhibitor 3-methyladenine (3-MA) dramatically increase PD-induced apoptosis as evidence by the increased percentage of apoptotic cell death. The anti-tumor effects of PD also investigated in vivo. The results showed that the combinatory treatment of PD with autophagy inhibitor significantly promote PD-induced apoptosis.

Conclusion: PD could induce caspase-dependent apoptosis and cyto-protectvie autophagy by activation of JNK1/Bcl-2 pathway in breast cancer cells. Combination with an autophagy inhibitor significantly enhance cytotoxic effect of PD and this combination may be a promising candidate for breast cancer therapy.
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http://dx.doi.org/10.1016/j.jep.2021.114591DOI Listing
September 2021

Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase.

Nat Nanotechnol 2021 Aug 5. Epub 2021 Aug 5.

Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.

Although nanomaterials have shown promising biomedical application potential, incomplete understanding of their molecular interactions with biological systems prevents their inclusion into mainstream clinical applications. Here we show that black phosphorus (BP) nanomaterials directly affect the cell cycle's centrosome machinery. BP destabilizes mitotic centrosomes by attenuating the cohesion of pericentriolar material and consequently leads to centrosome fragmentation within mitosis. As a result, BP-treated cells exhibit multipolar spindles and mitotic delay, and ultimately undergo apoptosis. Mechanistically, BP compromises centrosome integrity by deactivating the centrosome kinase polo-like kinase 1 (PLK1). BP directly binds to PLK1, inducing its aggregation, decreasing its cytosolic mobility and eventually restricting its recruitment to centrosomes for activation. With this mechanism, BP nanomaterials show great anticancer potential in tumour xenografted mice. Together, our study reveals a molecular mechanism for the tumoricidal properties of BP and proposes a direction for biomedical application of nanomaterials by exploring their intrinsic bioactivities.
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http://dx.doi.org/10.1038/s41565-021-00952-xDOI Listing
August 2021

A novel pyrrole-imidazole polyamide targets Aurora kinase A and suppresses tumor growth in vivo.

Biochem Biophys Res Commun 2021 Sep 27;571:167-173. Epub 2021 Jul 27.

Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address:

Aurora kinase A (Aurora A) plays a critical role in regulating cell mitotic progression and has been considered as a promising drug target for cancer therapy. To develop a novel molecule targeting Aurora A with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide (PIP) Hoechst conjugate, PIP-Ht, targeting to a cell-cycle regulated DNA sequence locating at the promoter of human Aurora A gene (AURKA). PIP-Ht potently suppressed AURKA promoter activities, mRNA expression and protein level, induced tumor cell cycle delay and inhibited tumor cell proliferation in vitro. Furthermore, subcutaneous injection of PIP-Ht into mice bearing human cancer xenografts induced significant tumor growth suppression and cell apoptosis. Collectively, PIP-Ht exhibits the potential as an effective therapeutic candidate for the tumor treatment.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.077DOI Listing
September 2021

Astragalus IV Undermines Multi-Drug Resistance and Glycolysis of MDA-MB-231/ADR Cell Line by Depressing hsa_circ_0001982-miR-206/miR-613 Axis.

Cancer Manag Res 2021 22;13:5821-5833. Epub 2021 Jul 22.

Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, 201100, People's Republic of China.

Background: Allowing for the power of astragalus in improving cancer patients' response to chemotherapy, we endeavored to clarify if hsa_circ_0001982-centered miRNA axes participated in the impact of astragaloside IV on multi-drug resistance (MDR) of triple-negative breast cancer (TNBC).

Methods: TNBC patients were recruited into an Astragalus detoxification decoction (ADD) treatment group (N=62) and a non-ADD treatment group (N=78), according to whether they consumed ADD after chemotherapy or not. Furthermore, drug resistance of the MDA-MB-231/ADR cell line in response to gemcitabine (GEM), adriamycin (ADM), oxaliplatin (OXA), and cisplatin (DDP) was evaluated, and glycolytic potential of MDA-MB-231/ADR cells was determined after astragaloside IV treatment or si-hsa_circ_0001982/miR-206 inhibitor/miR-613 inhibitor transfection.

Results: TNBC patients receiving ADD adjuvant therapy after chemotherapy, with decreased serum level of hsa_circ_0001982 and increased serum level of miR-206/miR-613 as relative to non-ADD treatment group (<0.05), were less likely to relapse than TNBC population not undergoing ADD treatment (<0.05). In addition, GEM/ADM/OXA/DDP-resistance and glycolysis of MDA-MB-231/ADR cell line were debilitated after exposure to astragaloside IV or transfection by si-hsa_circ_0001982 (<0.05). Nonetheless, miR-206/miR-613 inhibitor transfection reversed inhibitory effects of si-hsa_circ_0001982 and astragaloside IV on glycolysis and MDR of MDA-MB-231/ADR cell line (<0.05).

Conclusion: Astragaloside IV undermined MDR and glycolysis of MDA-MB-231/ADR cell line by blocking hsa_circ_0001982-miR-206/miR-613 axis.
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http://dx.doi.org/10.2147/CMAR.S297008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314933PMC
July 2021

Preimplantation genetic testing is not a preferred recommendation for patients with X chromosome abnormalities.

Hum Reprod 2021 Aug;36(9):2612-2621

Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Study Question: Should women with X chromosome abnormalities (XCAs) be recommended to have embryos selected by both morphological and cytogenetic assessment through preimplantation genetic testing (PGT) rather than morphological assessment only in conventional IVF/ICSI treatment?

Summary Answer: PGT is not a preferred recommendation for women with XCAs in the absence of other PGT indications.

What Is Known Already: XCAs are the most frequent sort of chromosomal aberrations in infertile women. Patients with a complete or partial absence of one X chromosome, diagnosed as Turner Syndrome (TS), demonstrate low spontaneous pregnancy rates (5-7%) and high miscarriage rates (22.8-30.8%), as well as high chances of birth defects (20%). PGT is known to improve pregnancy rates and decrease the incidence of miscarriage in couples with chromosomal aberrations such as Robertsonian and reciprocal translocations and Klinefelter Syndrome.

Study Design, Size, Duration: A retrospective cohort study was conducted with 394 women with XCAs and undergoing their first oocyte retrieval and first embryo transfer cycle from June 2011 to August 2019 in the Reproductive Hospital Affiliated to Shandong University.

Participants/materials, Setting, Methods: Pregnancy outcomes were compared between the conventional IVF/ICSI group (n = 284) and the PGT group (n = 110) in the first fresh or frozen embryo transfer cycle for each woman with XCAs. Three platforms were applied in PGT: fluorescence in situ hybridisation (FISH, n = 34), array comparative genomic hybridisation (aCGH, n = 24) and next-generation sequencing (NGS, n = 51). The embryo aneuploidy rate and distribution of embryonic chromosomal aberrations revealed by aCGH or NGS were analysed and stratified by maternal age and type of XCAs to assess the effect of maternal XCAs on embryo karyotypes.

Main Result And The Role Of Chance: The live birth rate (LBR) per embryo transfer was similar between the PGT group and IVF/ICSI group both in the first cycle of fresh or frozen embryo transfer respectively (39.13% in PGTFISH vs 42.58% in IVF/ICSI, Padj=0.558; 66.67% in PGTFISH vs 52.08% in PGTaCGH/NGS vs 53.06% in IVF/ICSI, Padj=0.756), as was the clinical pregnancy rate (60.87% in PGTFISH vs 50.97% in IVF/ICSI, Padj =0.672; 88.89% in PGTFISH vs 58.33% in PGTaCGH/NGS vs 69.39% in IVF/ICSI, Padj =0.480) and the pregnancy loss rate (35.71% in PGTFISH vs 16.46% in IVF/ICSI, Padj =0.136; 12.50% in PGTFISH vs 10.71% in PGTaCGH/NGS vs 23.53% in IVF/ICSI, Padj =0.352). The rates of maternal and neonatal complications were also comparable between the PGT and IVF/ICSI groups with fresh and frozen transfers respectively (10.00% vs 8.85%, P = 1.000; 21.74% vs 14.55%, P = 0.272). Intriguingly, the distribution of embryonic chromosome abnormalities was more frequent on autosomes 22 (20.39%), 21 (18.45%) and 16 (17.47%), compared with the X chromosome (8.73%).

Limitations, Reasons For Caution: Selection bias is an inherent drawback of a retrospective study. First, our participants hosted 4.84% X chromosome mosaicism with few typical somatic anomalies of TS. Second, the incidences of history of recurrent miscarriage and abnormal offspring in the PGT group were higher than in IVF/ICSI group although binary logistic regression analysis was performed to attenuate the modifying effect of confounding factors. Third, FISH performed in this study only used X/Y probes and lacked the reference of autosome, which might have resulted in misdiagnosis and bias. Finally, intrinsic disadvantages could not be totally avoided due to the retrospective nature of this study.

Wider Implication Of The Findings: In the current study, comparable pregnancy outcomes were revealed among a large cohort of women with XCAs undergoing their first cycles of PGT or conventional IVF/ICSI treatment. Moreover, the X chromosome abnormality was illustrated to cause no higher frequency of aberrations in embryos. Our data provided perspectives for genetic and reproductive counselling to XCAs individuals and their families.

Study Funding/competing Interest(s): This work was supported by National Research and Development Plan (2016YFC1000604 and 2017YFC1001100), the National Natural Science Foundation of China (81701406), Shandong Science Fund for Distinguished Young Scholars (JQ201720), Taishan Scholars Program for Young Experts of Shandong Province (tsqn20161069) and Projects of Medical and Health Technology Development Program in Shandong Province (202005010520, 202005010523 and 2016WS0368). There is no conflict of interest to declare.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373470PMC
August 2021

Reinforcing the Combinational Immuno-Oncotherapy of Switching "Cold" Tumor to "Hot" by Responsive Penetrating Nanogels.

ACS Appl Mater Interfaces 2021 Aug 27;13(31):36824-36838. Epub 2021 Jul 27.

Laboratory of Immunology and Nanomedicine, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.

Although immuno-oncotherapy in clinic has gained great success, the immunosuppressive tumor microenvironment (TME) existing in the "cold" tumor with insufficient and exhausted lymphocytes may result in a lower-than-expected therapeutic efficiency. Therefore, a properly designed synergistic strategy that can effectively turn the "cold" tumor to "hot" should be considered to improve the therapeutic effects of immuno-oncotherapy. Herein, TME-responsive penetrating nanogels (NGs) were developed, which can improve the delivery and penetration of the co-loaded resiquimod (R848) and green tea catechin (EGCG) in tumors by a nano-sized controlled releasing system of the soluble cyclodextrin-drug inclusion complex. Consequently, the NGs effectively promoted the maturation of dendritic cells, stimulated the cytotoxic T lymphocytes (CTLs), and decreased the PD-L1 expression in tumors. The combination of NGs with the OX40 agonist (αOX40) further synergistically enhanced the activation and infiltration of CTLs into the deep tumor and inhibited the suppression effects from the regulatory T cells (Tregs). As a result, an increased ratio of active CTLs to Tregs in tumors (20.66-fold) was achieved with a 91.56% tumor suppression effect, indicating a successful switch of "cold" tumors to "hot" for an immunologically beneficial TME with significantly improved anti-tumor immune therapeutics. This strategy could be tailored to other immuno-oncotherapeutic approaches to solve the urgent efficiency concerns of the checkpoint-based treatment in clinic.
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http://dx.doi.org/10.1021/acsami.1c08201DOI Listing
August 2021

Involvement of the VEGF signaling pathway in immunosuppression and hypoxia stress: analysis of mRNA expression in lymphocytes mediating panting in Jersey cattle under heat stress.

BMC Vet Res 2021 Jun 7;17(1):209. Epub 2021 Jun 7.

Department of Animal Science, Khon Kaen University, Kaen, 40002, Thailand.

Background: Extreme panting under heat stress threatens dairy cattle milk production. Previous research has revealed that the gas exchange-mediated respiratory drive in critically ill dairy cattle with low O saturation induces panting. Vascular endothelial growth factor (VEGF) signaling may play important roles in immunosuppression and oxidative stress during severe respiratory stress responses in heat-stressed cattle. The objectives of this study were to transcriptomically analyze mRNA expression mediating heat-induced respiratory stress-associated panting, evaluate gas exchange, screen hub genes, and verify the expression of proteins encoded by differentially expressed genes in lymphocyte pathways.

Results: Jersey cattle were naturally heat-exposed. Physiological data were collected for response evaluation, and blood was collected for gas exchange and gene expression assays at 06:00, 10:00 and 14:00 continuously for 1 week. Lymphocytes were isolated from whole-blood samples for mRNA-seq and expression analysis of key pathway genes/proteins. The cattle respiration rates differed with time, averaging 51 bpm at 06:00, 76 bpm at 10:00, and 121 bpm at 14:00 (p < 0.05). Gas exchange analysis showed that both pH and pCO differed with time: they were 7.41 and 41 mmHg at 06:00, 7.45 and 37.5 mmHg at 10:00, and 7.49 and 33 mmHg at 14:00, respectively (p < 0.01). Sixteen heat-related differentially expressed genes (DEGs; 13 upregulated and 3 downregulated) were screened between 212 DEGs and 1370 heat stress-affected genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) hub gene functional analysis annotated eleven genes to signal transduction, six genes to the immune response, and five genes to the endocrine response, including both prostaglandin-endoperoxide synthase 2 (PTGS2) and VEGF. Gene Ontology (GO) functional enrichment analysis revealed that oxygen regulation was associated with the phosphorus metabolic process, response to oxygen levels, response to decreased oxygen levels, response to hypoxia and cytokine activity terms. The main signaling pathways were the VEGF, hypoxia inducible factor-1(HIF-1), cytokine-cytokine receptor interaction and TNF pathways. Four genes involved Integrin beta 3 (ITBG3), PTGS2, VEGF, and myosin light chain 9 (MYL9) among the 16 genes related to immunosuppression, oxidative stress, and endocrine dysfunction were identified as participants in the VEGF signaling pathway and oxygenation.

Conclusion: These findings help elucidate the underlying immune and oxygen regulation mechanisms associated with the VEGF signaling pathway in heat-stressed dairy cattle.
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http://dx.doi.org/10.1186/s12917-021-02912-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186226PMC
June 2021

Tyrosine-Specific Modification via a Dearomatization-Rearomatization Strategy: Access to Azobenzene Functionalized Peptides.

Org Lett 2021 Jun 19;23(11):4137-4141. Epub 2021 May 19.

Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.

Azobenzene functionalized peptides are of great importance in photoresponsive biosystems and photopharmacology. Herein, we report an efficient approach to prepare azobenzene functionalized peptides through late-stage modification of tyrosine-containing peptides using a dearomatization-rearomatization strategy. This approach shows good chemoselectivity and site selectivity as well as sensitive group tolerance to various peptides. This method enriches the postsynthetic modification toolbox of peptides and has great potential to be applied in medicinal chemistry and chemical biology.
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http://dx.doi.org/10.1021/acs.orglett.1c01013DOI Listing
June 2021

Tripartite motif-containing protein 6 facilitates growth and migration of breast cancer through degradation of STUB1.

Eur J Histochem 2021 Mar 10;65(1). Epub 2021 Mar 10.

Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai.

Proteins in the tripartite motif-containing protein (TRIM) family participates in carcinogenesis. However, little attention was focused on the role of TRIM6 on development of breast cancer. Expression level of TRIM6 was found to be markedly enhanced in breast cancer cells and tissues. Functional assays demonstrated that overexpression of TRIM6 promoted breast cancer progression through increase of YAP1 (Yes-associated Protein 1), while knockdown of TRIM6 suppressed in vitro breast cancer progression and in vivo tumor growth through decrease of YAP1. Co-Immunoprecipitation (co-IP) showed that TRIM6 interacted with STUB1 (stress induced phosphoprotein 1 homology and U-box containing protein 1). TRIM6 promoted ubiquitination-mediated degradation of STUB1 to promote YAP1 signaling. Overexpression of STUB1 attenuated TRIM6-induced promotion of breast cancer growth. In conclusion, TRIM6 contributed to breast cancer progression through ubiquitination-dependent proteasomal degradation of STUB1 and provocation of YAP1 pathway, providing potential therapeutic target for breast cancer.
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http://dx.doi.org/10.4081/ejh.2021.3214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967267PMC
March 2021

Effects of PGT-A on Pregnancy Outcomes for Young Women Having One Previous Miscarriage with Genetically Abnormal Products of Conception.

Reprod Sci 2021 Mar 15. Epub 2021 Mar 15.

Center for Reproductive Medicine, Shandong University, 157 Jingliu Road, Jinan, 250012, Shandong, China.

In this retrospective study, the effect of preimplantation genetic testing for aneuploidy (PGT-A) was evaluated in women younger than 38 years with a history of one prior miscarriage and embryonic chromosomal abnormalities were detected in previous products of conception (POCs). Abnormal karyotypes were detected in POCs at our center between January 2014 and December 2017. Of the women included in this analysis, 124 continued with conventional in vitro fertilization/intracytoplasmic sperm injection cycles (non-PGT-A group) and 93 chose PGT-A cycles (PGT-A group), and the pregnancy outcomes in both groups were compared. Although the clinical pregnancy rate per embryo transfer was significantly higher in the PGT-A group (67.23% vs. 51.85%, p-adj = 0.01), no between-group differences were found in the live birth rate or miscarriage rate (45.38% vs. 40.74%, p-adj = 0.59; 16.25% vs. 14.29%, p-adj = 0.15). Women in both groups had comparative cumulative live birth rates (PGT-A vs. non-PGT-A, 58.06% vs. 53.23%, p = 0.48). The main results of this study suggest that PGT-A is not associated with an increased likelihood of a live birth or a decreased rate of miscarriage among women younger than 38 years without recurrent pregnancy loss and with a history of POCs with embryonic chromosomal abnormalities.
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http://dx.doi.org/10.1007/s43032-021-00542-1DOI Listing
March 2021

Coibamide A kills cancer cells through inhibiting autophagy.

Biochem Biophys Res Commun 2021 04 13;547:52-58. Epub 2021 Feb 13.

Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address:

Natural products are useful tools for biological mechanism research and drug discovery. Due to the excellent tumor cell growth inhibitory profile and sub-nanomolar potency, Coibamide A (CA), an N-methyl-stabilized depsipeptide isolated from marine cyanobacterium, has been considered as a promising lead compound for cancer treatment. However, the molecular anti-cancer mechanism of the action of CA remains unclear. Here, we showed that CA treatment induced caspase-independent cell death in breast cancer cells. CA treatment also led to severe lysosome defects, which was ascribed to the impaired glycosylation of lysosome membrane protein LAMP1 and LAMP2. As a consequence, the autophagosome-lysosome fusion was blocked upon CA treatment. In addition, we presented evidence that this autophagy defect partially contributed to the CA treatment-induced tumor cell death. Together, our work uncovers a novel mechanism underlying the anti-cancer action of CA, which will promote its further application for cancer therapy.
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http://dx.doi.org/10.1016/j.bbrc.2021.01.112DOI Listing
April 2021

Author Correction: Neddylation of PTEN regulates its nuclear import and promotes tumor development.

Cell Res 2021 Mar;31(3):374

State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.

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http://dx.doi.org/10.1038/s41422-021-00470-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027785PMC
March 2021

Hsa_circ_0000199 facilitates chemo-tolerance of triple-negative breast cancer by interfering with miR-206/613-led PI3K/Akt/mTOR signaling.

Aging (Albany NY) 2021 01 20;13(3):4522-4551. Epub 2021 Jan 20.

Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai 201100, China.

Increasing attentions have been paid to the role of circRNAs in the etiology of triple-negative breast cancer (TNBC), and we strived to figure out the association of circRNA AKT3/miRNA axis with TNBC chemo-resistance. Altogether 207 BC patients were divided into TNBC group (n=83) and non-TNBC group (n=124), and MCF-10A, MDA-MB-231, MDA-MB-468, SK-BR-3 and MCF-7 cell lines were prepared in advance. Expressions of AKT3-derived circRNAs and relevant miRNAs in the TNBC tissues and cell lines were determined by employing real-time polymerase chain reaction (PCR). It was indicated that hsa_circ_0000199 expression was higher in TNBC tissues than in non-TNBC tissues, and high hsa_circ_0000199 expression was predictive of large tumor size, advanced TNM grade, high Ki-67 level and poor 3-year survival of TNBC patients (all <0.05). Furthermore, miR-613 and miR-206 were sponged and negatively regulated by hsa_circ_0000199 (<0.001), and PI3K/Akt/mTOR signaling was depressed by si-hsa_circ_0000199 in TNBC cell lines (<0.01). Ultimately, miR-206/miR-613 inhibitor reversed impacts of si-hsa_circ_0000199 on PI3K/Akt/mTOR signaling, proliferation, migration, invasion, chemo-sensitivity and autophagy of TNBC cells (all <0.01). Conclusively, silencing of hsa_circ_0000199 enhanced TNBC chemo-sensitivity by promoting miR-206/miR-613 expression and deactivating PI3K/Akt/mTOR signaling, which was conducive to improving chemotherapeutic efficacy of TNBC patients.
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http://dx.doi.org/10.18632/aging.202415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906206PMC
January 2021

Novel -Methylated Cyclodepsipeptide Prodrugs for Targeted Cancer Therapy.

J Med Chem 2021 01 8;64(2):991-1000. Epub 2021 Jan 8.

Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.

Coibamide A () is a highly -methylated cyclodepsipeptide with low nanomolar antiproliferative activities against various cancer cell lines. In previous work, we discovered a simplified analogue, [MeAla3-MeAla6]-coibamide (), which exhibited the same inhibitory abilities as coibamide A. Herein, to reduce the whole-body toxicity and improve the solubility of , two novel peptide-drug conjugates RGD-SS-CA () and RGD-VC-CA () were designed, synthesized, and evaluated. Composed of cyclodepsipeptide , a tumor-homing RGD motif, and a conditionally labile linker, the conjugates are expected to release tracelessly in specific tumor microenvironments. Compared with RGD-VC-CA (), RGD-SS-CA () proved to be superior in in vitro drug release and cytotoxicity tests. Notably, intravenous injection of RGD-SS-CA () into mice-bearing human tumor xenografts induced significant tumor growth suppression with negligible toxicity. Therefore, as a novel prodrug of the coibamide A analogue, conjugate has great potential for further exploration in cancer drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01387DOI Listing
January 2021

DCAF13 promotes triple-negative breast cancer metastasis by mediating DTX3 mRNA degradation.

Cell Cycle 2020 12 10;19(24):3622-3631. Epub 2020 Dec 10.

Department of General Surgery, Minhang Hospital, Fudan University , Shanghai, China.

DCAF13 is firstly identified as a substrate receptor of CUL4-DDB1 E3 ligase complex. This study disclosed that DCAF13 acted as a novel RNA binding protein (RBP) that contributed to triple-negative breast cancer (TNBC) metastasis. Clinical data obtained from TCGA and our collection showed that DCAF13 was closely correlated with poor clinicopathological characteristics and overall survival, which indicated DCAF13 may serve as a diagnostic marker for TNBC metastasis. Functionally, DCAF13 overexpression or suppression was sufficient to enhance or decrease breast cancer cell migration and invasion. Mechanistically, DCAF13 functioned as an RBP by binding with the AU-rich element (ARE) of DTX3 mRNA 3'UTR to accelerate its degradation. Moreover, we identified that DTX3 promoted the ubiquitination and degradation of NOTCH4. Finally, increased DCAF13 expression led to post-transcriptional decay of DTX3 mRNA and consequently activated of NOTCH4 signaling pathway in TNBC. In conclusion, these results identified that DCAF13 as a diagnostic marker and therapeutic target for TNBC treatment. DCAF13: DDB1 and CUL4-associated factor 13; DDB1: DNA-binding protein 1; CUL4: Cullin 4; CRL4, Cullin-ring finger ligase 4; RBP: RNA binding protein; TNBC: triple-negative breast cancer; ARE: AU-rich element; DTX3: Deltex E3 ubiquitin ligase 3; HER2: human epidermal growth factor receptor 2; ER: estrogen receptor; PR: progesterone receptor; PTEN: phosphatase and tensin homolog deleted on chromosome 10; EMT: epithelial-mesenchymal transition.
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http://dx.doi.org/10.1080/15384101.2020.1859196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781530PMC
December 2020

Neddylation of PTEN regulates its nuclear import and promotes tumor development.

Cell Res 2021 03 9;31(3):291-311. Epub 2020 Dec 9.

State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.

PTEN tumor suppressor opposes the PI3K/Akt signaling pathway in the cytoplasm and maintains chromosomal integrity in the nucleus. Nucleus-cytoplasm shuttling of PTEN is regulated by ubiquitylation, SUMOylation and phosphorylation, and nuclear PTEN has been proposed to exhibit tumor-suppressive functions. Here we show that PTEN is conjugated by Nedd8 under high glucose conditions, which induces PTEN nuclear import without effects on PTEN stability. PTEN neddylation is promoted by the XIAP ligase and removed by the NEDP1 deneddylase. We identify Lys197 and Lys402 as major neddylation sites on PTEN. Neddylated PTEN accumulates predominantly in the nucleus and promotes rather than suppresses cell proliferation and metabolism. The nuclear neddylated PTEN dephosphorylates the fatty acid synthase (FASN) protein, inhibits the TRIM21-mediated ubiquitylation and degradation of FASN, and then promotes de novo fatty acid synthesis. In human breast cancer tissues, neddylated PTEN correlates with tumor progression and poor prognosis. Therefore, we demonstrate a previously unidentified pool of nuclear PTEN in the Nedd8-conjugated form and an unexpected tumor-promoting role of neddylated PTEN.
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http://dx.doi.org/10.1038/s41422-020-00443-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027835PMC
March 2021

circFAT1(e2) Promotes Papillary Thyroid Cancer Proliferation, Migration, and Invasion via the miRNA-873/ZEB1 Axis.

Comput Math Methods Med 2020 19;2020:1459368. Epub 2020 Oct 19.

Minhang Hospital, Fudan University, 170 Xin-Song Road, Shanghai 201199, China.

Circular RNAs (circRNAs) play an extremely important regulatory role in the occurrence and development of various malignant tumors including papillary thyroid cancer (PTC). circFAT1(e2) is a new type of circRNA derived from exon 2 of the FAT1 gene, which is distributed in the cytoplasm and nucleus of PTC cells. However, so far, the role of circFAT1(e2) in PTC is still unclear. In this study, circFAT1(e2) was found to be highly expressed in PTC cell lines and tissues. circFAT1(e2) knockdown suppressed PTC cell growth, migration, and invasion. Also, circFAT1(e2) acted as a sponge for potential microRNAs (miRNAs) to modulate cancer progression. A potential miRNA target was discovered to be miR-873 which was targeted by circFAT1(e2) in PTC. The dual-luciferase assay conducted later also confirmed that there was indeed a direct interaction between circFAT1(e2) and miR-873. This study also confirmed that circFAT1(e2) inhibited the miR-873 expression and thus promoted the ZEB1 expression, thus affecting the proliferation, metastasis, and invasion of PTC cells. In conclusion, the results of this study indicated that circFAT1(e2) played a carcinogenic role by targeting the miR-873/ZEB1 axis to promote PTC invasion and metastasis, which might become a potential novel target for therapy of PTC.
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http://dx.doi.org/10.1155/2020/1459368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593750PMC
July 2021

Clinical outcomes of Preimplantation genetic testing (PGT) application in couples with chromosomal inversion, a study in the Chinese Han population.

Reprod Biol Endocrinol 2020 Aug 5;18(1):79. Epub 2020 Aug 5.

Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.

Background: Chromosomal inversion was considered to have adverse effects on pregnancy outcomes through abnormal gametogenesis. The purpose of this retrospective study was to investigate whether preimplantation genetic testing (PGT) improves pregnancy outcomes for couples with chromosomal inversion.

Methods: A total of 188 cycles from 165 couples with one chromosomal inversion carrier were divided into two groups: PGT (136 cycles, 125 couples) and non-PGT (52 cycles, 50 couples). Biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and live birth rates of their first transfer cycles, as well as cumulative live birth rates of each cycle and euploidy rates, were analyzed.

Results: There were no statistically significant differences in the pregnancy outcomes between the two groups. The euploidy rate of pericentric inversion carriers was not higher than that of paracentric inversion carriers in PGT group (60.71% vs 50.54%, P = 0.073). Similarly, the euploid rate of male carriers was not higher than that of female carriers (61.2% vs 56.1%, P = 0.256).

Conclusions: Due to limitation of retrospective study and small sample size, our current data showed that PGT cannot provide prominent benefits for inversion carriers in the Chinese Han population. Further prospective randomized controlled trials are needed to evaluate the effects of PGT.
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http://dx.doi.org/10.1186/s12958-020-00635-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405424PMC
August 2020

Chlorotoxin-derived bicyclic peptides for targeted imaging of glioblastomas.

Chem Commun (Camb) 2020 Aug;56(66):9537-9540

Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. and University of Chinese Academy of Sciences, Beijing 100049, China.

A convenient and efficient strategy was developed for accessing chlorotoxin-derived bicyclic peptide-biomolecule conjugates by cyclizing fully-unprotected linear peptides with a designed tetrafunctional chemical linker. Among these peptides, bicycle-P3 bearing the N-terminal sequence of chlorotoxin shows high tumor selectivity and penetration ability, which is promising for treatment of gliomas.
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http://dx.doi.org/10.1039/d0cc01089hDOI Listing
August 2020

Hypermethylation of lncRNA MEG3 impairs chemosensitivity of breast cancer cells.

J Clin Lab Anal 2020 Sep 3;34(9):e23369. Epub 2020 Jul 3.

Department of General Surgery, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, China.

Background: Chemoresistance posed a barrier to successful treatment of breast cancer (BC), and lncRNA MEG3 has been documented to implicate in BC development. However, whether MEG3 methylation, which led to low MEG3 expression, was relevant to BC progression and chemoresistance remained uncertain.

Methods: In the aggregate, 374 pairs of tumor tissues and adjacent normal tissues were collected from pathologically confirmed BC patients, and four BC cell lines, including MDA-MB-231, Bcap-37, MCF-7, and SK-BR-3, were purchased. Moreover, methylation-specific polymerase chain reaction (PCR) was adopted to evaluate the methylation status of BC tissues and cell lines, and chemo-tolerance of BC cell lines was assessed by performing MTT assay. Concurrently, transwell assay and scratch assay were carried out to estimate the migratory and invasive capability of BC cell lines.

Results: Methylated MEG3, lowly expressed MEG3, large tumor size (≥2 cm), advanced TNM grade and lymphatic metastasis were potentially symbolic of poor prognosis among BC patients (P < .05). Besides, MDA-MB-231 cell line exhibited the strongest resistance against paclitaxel, adriamycin, and vinorelbine (P < .05), while MCF-7 cell line seemed more sensitive against these drugs than any other BC cell line (P < .05). Furthermore, pcDNA3.1-MEG3 and 5-Aza-dC markedly sensitized MDA-MB-231 and MCF-7 cell lines against the drug treatments (P < .05). Simultaneously, proliferation and metastasis of the BC cell lines were slowed down under the force of pcDNA3.1-MEG3 and 5-Aza-dC (P < .05).

Conclusion: Preventing methylation of MEG3 might matter in lessening BC chemoresistance, owing to its hindering proliferation and metastasis of BC cells.
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http://dx.doi.org/10.1002/jcla.23369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521317PMC
September 2020

Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer.

Cell Death Differ 2020 11 1;27(11):3177-3195. Epub 2020 Jun 1.

State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.

Ovarian tumour domain-containing protein 3 (OTUD3), a key OTU (ovarian tumour protease) family deubiquitylase, plays context-dependent roles in cancers. It suppresses tumorigenesis in breast, colon, liver and cervical cancer through stabilizing PTEN (phosphatase and tension homologue deleted on chromosome 10) while promotes lung tumorigenesis through stabilizing GRP78 (The glucose-regulated protein 78 kDa). The regulation especially post-translational modification of OTUD3 remains unclear. Here, we report that the carboxyl terminus of Hsc70-interacting protein (CHIP) is a ubiquitin ligase for OTUD3. CHIP interacts with, polyubiquitylates OTUD3 and promotes OTUD3 degradation. Knockdown of CHIP stabilizes OTUD3 which leads to elevated GRP78 levels in lung cancer cells. CHIP-knockdown lung cancer cells exhibit increased invasion in OTUD3 and GRP78 dependent manner. Further study demonstrates that CHIP-knockdown lung cancer cells are more prone to metastasize to mice lung when injected intravenously or subcutaneously. Moreover, the expression of CHIP is low in human lung cancer tissues and inversely correlates with OTUD3 expression and GRP78 expression. Furthermore, we identified CHIP mutations in human lung cancers, which reduce CHIP catalytic activity. These findings demonstrate that CHIP is a negative regulator of OTUD3 and CHIP suppresses lung cancer metastasis through inhibiting OTUD3-GRP78 signaling axis.
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http://dx.doi.org/10.1038/s41418-020-0571-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560627PMC
November 2020

TRIM25 promotes the cell survival and growth of hepatocellular carcinoma through targeting Keap1-Nrf2 pathway.

Nat Commun 2020 01 17;11(1):348. Epub 2020 Jan 17.

Shenzhen Laboratory of Tumor Cell Biology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, P. R. China.

Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.
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http://dx.doi.org/10.1038/s41467-019-14190-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969153PMC
January 2020

A novel machine learning based approach for iPS progenitor cell identification.

PLoS Comput Biol 2019 12 26;15(12):e1007351. Epub 2019 Dec 26.

Joint Engineering Research Center for Health Big Data Intelligent Analysis Technology, Center for High Performance Computing, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.

Identification of induced pluripotent stem (iPS) progenitor cells, the iPS forming cells in early stage of reprogramming, could provide valuable information for studying the origin and underlying mechanism of iPS cells. However, it is very difficult to identify experimentally since there are no biomarkers known for early progenitor cells, and only about 6 days after reprogramming initiation, iPS cells can be experimentally determined via fluorescent probes. What is more, the ratio of progenitor cells during early reprograming period is below 5%, which is too low to capture experimentally in the early stage. In this paper, we propose a novel computational approach for the identification of iPS progenitor cells based on machine learning and microscopic image analysis. Firstly, we record the reprogramming process using a live cell imaging system after 48 hours of infection with retroviruses expressing Oct4, Sox2 and Klf4, later iPS progenitor cells and normal murine embryonic fibroblasts (MEFs) within 3 to 5 days after infection are labeled by retrospectively tracing the time-lapse microscopic image. We then calculate 11 types of cell morphological and motion features such as area, speed, etc., and select best time windows for modeling and perform feature selection. Finally, a prediction model using XGBoost is built based on the selected six types of features and best time windows. Our model allows several missing values/frames in the sample datasets, thus it is applicable to a wide range of scenarios. Cross-validation, holdout validation and independent test experiments show that the minimum precision is above 52%, that is, the ratio of predicted progenitor cells within 3 to 5 days after viral infection is above 52%. The results also confirm that the morphology and motion pattern of iPS progenitor cells is different from that of normal MEFs, which helps with the machine learning methods for iPS progenitor cell identification.
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http://dx.doi.org/10.1371/journal.pcbi.1007351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932749PMC
December 2019

Material basis and molecular mechanisms of Dachengqi decoction in the treatment of acute pancreatitis based on network pharmacology.

Biomed Pharmacother 2020 Jan 23;121:109656. Epub 2019 Nov 23.

Department of general surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China. Electronic address:

Background: Dachengqi decoction (DCQD) is a classical prescription in traditional Chinese medicine (TCM). It has been used to treat abdominal pain and acute pancreatitis (AP) for thousands of years in China.

Objective: To predict the active components and signaling pathway of DCQD and to further explore the potential molecular mechanism of DCQD as a treatment of AP using network pharmacology.

Methods: Network pharmacology and bioinformatics were used to determine the active components of DCQD and its potential target in the treatment of AP. The AP model was induced by Cerulein (Cer) combined with lipopolysaccharide (LPS). The pharmacodynamic basis of DCQD in the treatment of AP was evaluated in vitro and in vivo and Western blot analysis and immunofluorescence were used to determine the molecular mechanism of DCQD.

Results: Screening using relevant databases and topological analysis revealed 71 active components and 535 potential target proteins in DCQD. In addition, 445 differential genes for AP were also screened. Pathway enrichment analysis, PPI network analysis and transcription factor prediction showed that DCQD played an important role in the PI3K-Akt signal pathway, and 17 DCQD monomers were found in this signal pathway. In the AP model, DCQD promoted pancreatic acinar cell apoptosis, reduction in inflammation, and regulation of the PI3K-AKT signaling pathway. DCQD inhibited the expression of p-AKT and p- NF-kB proteins in pancreatic tissue of the AP model both in vitro and in vivo.

Conclusion: This study reveals that 17 active components of DCQD improve AP by regulating the PI3K/AKT signaling pathway and promoting apoptosis and suppressing pathological injury and inflammation.
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http://dx.doi.org/10.1016/j.biopha.2019.109656DOI Listing
January 2020

The deubiquitinase USP10 regulates KLF4 stability and suppresses lung tumorigenesis.

Cell Death Differ 2020 06 20;27(6):1747-1764. Epub 2019 Nov 20.

Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044, China.

Krüppel-like factor 4 (KLF4), a key transcription factor, acts as a multifunctional player involved in the progression of numerous aggressive cancers. The proteasome-dependent pathway is one of the main modalities in controlling KLF4 abundance at a posttranslational level. Although some of the ubiquitin ligases have been identified, the deubiquitinases of KLF4 and the regulatory function remain unexplored. Here, by screening ubiquitin-specific proteases that may interact with KLF4, we found ubiquitin-specific peptidase 10 (USP10) as a deubiquitinating enzyme for KLF4. Forced expression of USP10 remarkably increases KLF4 protein level by blocking the latter degradation, whereas the depletion of USP10 promotes KLF4 degradation and thus enhances tumorigenesis. Loss of USP10 in mice downregulates KLF4 expression and accelerates Kras-driven lung adenocarcinoma initiation and progression. In addition, our data revealed that KLF4 can facilitate the transcription of tumor suppressor TIMP3 by directly binding to the TIMP3 promoter. Clinically, reduction of USP10 expression, concomitant with decreased KLF4 and TIMP3 abundance in carcinoma tissue, predicts poor prognosis of lung cancer patient. Taken together, our results demonstrate that USP10 is a critical regulator of KLF4, pinpointing USP10-KLF4-TIMP3 axis as a promising therapeutic target in lung cancer.
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http://dx.doi.org/10.1038/s41418-019-0458-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244734PMC
June 2020

Pregnancy outcomes of reciprocal translocation carriers with two or more unfavorable pregnancy histories: before and after preimplantation genetic testing.

J Assist Reprod Genet 2019 Nov 14;36(11):2325-2331. Epub 2019 Sep 14.

Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200000, China.

Purpose: To report the normal live birth and birth defect rates pre- and post- preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) in reciprocal translocation carriers who have experienced two or more unfavorable pregnancy histories.

Methods: We conducted a retrospective cohort study of 194 couples who underwent 265 PGT-SR cycles between January 2013 and August 2016. The rates of miscarriage, normal live birth, and birth defect pre- and post- PGT-SR treatment were recorded. The types of birth defect were also categorized.

Results: Before PGT-SR treatment, the 194 couples with reciprocal translocation had a previous reproductive history consisting of 592 pregnancies in total: 496 (83.8%) were miscarriages; 29 (4.9%) ended by induced abortion due to unintended pregnancy; 36 (6.1%) had birth defects; and 17 (2.9%) were normal live births. After PGT-SR treatment, there were 118 clinical pregnancies. Of these pregnancies, 13 (11.0%) were miscarriages, 101 (85.6%) were normal live births, and 4 (3.4%) had birth defects. In total, 14 different disorders were noted in the prenatal and postnatal examinations. Before the PGT-SR treatment, multiple birth defects, central nervous system abnormalities, and congenital heart defects were the three most common congenital malformations. Excluding for methylmalonic acidemia, there were only single and mild birth defects after the PGT-SR treatment.

Conclusions: After the PGT-SR treatment, the reciprocal translocation carriers who had previously experienced two or more unfavorable pregnancy outcomes had a low risk of miscarriages and birth defects. The rate of normal live births per pregnancy was higher after PGT-SR treatment.
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http://dx.doi.org/10.1007/s10815-019-01585-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885462PMC
November 2019

Functional analysis of deubiquitylating enzymes in tumorigenesis and development.

Biochim Biophys Acta Rev Cancer 2019 12 23;1872(2):188312. Epub 2019 Aug 23.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Deubiquitylating enzymes (DUBs) are proteases that remove the ubiquitin moiety from ubiquitylated substrates to antagonize the modification mediated by E3 ubiquitin ligases. Currently, DUBs have been found to play critical roles in the regulation of various physiological or pathological processes, such as embryogenesis, immune homeostasis, tumorigenesis and neurodegenerative diseases. Accumulating evidences have suggested that different DUBs exert distinct function such as oncogenic, tumor-suppressive or context-dependent roles in tumorigenesis, mainly by affecting the protein stability, enzymatic activity or subcellular localization of its substrates. Importantly, multiple potent inhibitors targeting the enzymatic activity of oncogenic DUBs have been developed and show promising anti-cancer efficacy in preclinical models. Thus, exploring the unique role of DUB enzymes and their downstream effectors will provide novel insights into the molecular basis of cancer development. Here, we review and summarize recent progress on DUB functional annotation, as well as its biochemical regulation, to provide a better understanding for cancer therapies by targeting DUBs.
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http://dx.doi.org/10.1016/j.bbcan.2019.188312DOI Listing
December 2019

The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis.

Nat Commun 2019 07 2;10(1):2914. Epub 2019 Jul 2.

State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.

The deubiquitylase OTUD3 plays a suppressive role in breast tumorigenesis through stabilizing PTEN protein, but its role in lung cancer remains unclear. Here, we demonstrate that in vivo deletion of OTUD3 indeed promotes breast cancer development in mice, but by contrast, it slows down Kras-driven lung adenocarcinoma (ADC) initiation and progression and markedly increases survival in mice. Moreover, OTUD3 is highly expressed in human lung cancer tissues and its higher expression correlates with poorer survival of patients. Further mechanistic studies reveal that OTUD3 interacts with, deubiquitylates and stabilizes the glucose-regulated protein GRP78. Knockdown of OTUD3 results in a decrease in the level of GRP78 protein, suppression of cell growth and migration, and tumorigenesis in lung cancer. Collectively, our results reveal a previously unappreciated pro-oncogenic role of OTUD3 in lung cancer and indicate that deubiquitylases could elicit tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.
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http://dx.doi.org/10.1038/s41467-019-10824-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606649PMC
July 2019

Author Correction: Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation.

Nat Commun 2019 01 8;10(1):173. Epub 2019 Jan 8.

State Key Laboratory of Proteomics, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.

The original version of this Article contained an error in Figure 7. In panel c, the lanes of the western blots were incorrectly labelled '+/+ +/+ -/- -/- +/+ +/+ -/- -/-'. This has been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07984-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325103PMC
January 2019

Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation.

Nat Commun 2018 11 7;9(1):4648. Epub 2018 Nov 7.

State Key Laboratory of Proteomics, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China.

Sox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4A and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4A and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs.
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http://dx.doi.org/10.1038/s41467-018-07025-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220269PMC
November 2018
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