USP37 promotes deubiquitination of HIF2α in kidney cancer

Hong, Kai; Hu, Lianxin; Liu, Xijuan; Simon, Jeremy M.; Ptacek, Travis; Zheng, Xingnan; Liao, Chengheng; Baldwin, Albert S.; Zhang, Qing

doi:10.1073/pnas.2002567117

Cited by 35 publications

(32 citation statements)

References 32 publications

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“…By in vivo assay, USP37 downregulation also suppressed the tumor growth of MCF-7/ADR cells. The results are consistent with the previous reports that USP37 knockdown significantly inhibited the tumor formation of malignancies, such as lung cancer 18 , kidney cancer 19 , hepatocellular cancer 20 . Inordinate cell cycle progression resulted in tumorigenesis 21 .…”

Section: Discussionsupporting

confidence: 93%

USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin

Qin¹,

Cui²,

Xiu³

et al. 2021

Int. J. Med. Sci.

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Background: The evolution of adriamycin (ADR) resistance in the treatment of breast cancer often leads to a poor prognosis in patients. Ubiquitin-specific peptidase 37 (USP37) has been recently identified as a modulator in regulating the stemness of breast cancer cells, but its underlying mechanism remains unclear. In this study, we investigated whether USP37 knockdown could hamper the chemical resistance of MCF-7 and MCF-7/ADR cells to adriamycin and elucidated the potential mechanism. Methods: Immunohistochemistry, western blotting, and RT-qPCR assays were performed to detect the USP37 expression in MCF-7 and MCF-7/ADR cells. The efficiency of USP37 knockdown in breast cancer cells was confirmed by western blotting and RT-qPCR assays. We also performed CCK-8 assay, flow cytometry, western blotting, and TUNEL assays to evaluate cell viability and apoptosis in breast cancer cells. In vivo study was performed to detect the tumorigenicity of MCF-7/ADR cells transfected with shScramble or shUSP37#1 under adriamycin treatment. Results: Bioinformatic analysis indicated that USP37 overexpression was positively correlated with adriamycin resistance. The expression levels of USP37 in both MCF-7 and MCF-7/ADR cells increased significantly with the exposure to adriamycin in a dose-dependent manner. It was verified by the observation that USP37 downregulation elevated the inhibitory effects of adriamycin on breast cancer cells, suppressed cell proliferation caused by cell cycle arrest in G1/S transition, as well as induced apoptosis. Furthermore, in vivo study showed that knockdown of USP37 expression also decreased tumorigenicity of MCF-7/ADR cells in mice. TUNEL assay and observation of cell morphology magnified USP37 knockdown synergized with Adriamycin could elevate the apoptosis of MCF-7 and MCF-7/ADR cells. Western blotting assay illustrated that the combination of USP37 knockdown with adriamycin treatment significantly upregulated the expression levels of cleaved caspase 3 and Bax, whereas the expression level of Bcl-2 was inhibited. Conclusion: Knockdown of USP37 gene expression can reverse the resistance of breast cancer cells to adriamycin, and down-regulating USP37 might be a valuable strategy against ADR resistance in breast cancer therapy.

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Section: Discussionsupporting

confidence: 93%

USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin

Qin¹,

Cui²,

Xiu³

et al. 2021

Int. J. Med. Sci.

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“…As early as 1991, Kanayama had explored the changes in expressions of ubiquitin and proteasome genes in renal cancer cells by Northern blot as well as immunochemical analysis, and they drew a conclusion that the ubiquitin and proteasome system should play a role in the renal cancer [36]. In the past few decades, researchers have made great efforts to uncover the underlying mechanism of the UPS in the development of ccRCC [37][38][39][40][41]. It is indisputable that we have made tremendous achievements in this field, however, on the other hand, it is unanimously agreed that there remain enormous appealing mechanisms waiting us to uncover.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Role of the Ubiquitin Proteasome System in Clear Cell Renal Cell Carcinoma: A Bioinformatic Perspective

Guo¹,

Li²,

Liu³

et al. 2021

J. Cancer

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Background: Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor of the urinary system. The ubiquitin proteasome system (UPS) plays an important role in the generation, metabolism and survival of tumor. We are aimed to make a comprehensive exploration of the UPS's role in ccRCC with bioinformatic tools, which may contribute to the understanding of UPS in ccRCC, and give insight for further research. Methods: The UPS-related genes (UPSs) were collected by an integrative approach. The expression and clinical data were downloaded from TCGA database. R soft was used to perform the differentially expressed UPSs analysis, functional enrichment analysis. We also estimated prognostic value of each UPS with the help of GEPIA database. Two predicting models were constructed with the differentially expressed UPSs and prognosis-related genes, respectively. The correlations of risk score with clinical characteristics were also evaluated. Data of GSE29609 cohort were obtained from GEO database to validate the prognostic models. Results: We finally identified 91 differentially expressed UPSs, 48 prognosis related genes among them, and constructed a prognostic model with 18 UPSs successfully, the AUC was 0.760. With the help of GEPIA, we found 391 prognosis-related UPSs, accounting for 57.84% of all UPSs. Another prognostic model was constructed with 28 prognosis-related genes of them, and with a better AUC of 0.825. Additionally, our models can also stratify patients into high and low risk groups accurately in GSE29609 cohort. Similar prognostic values of our models were observed in the validated GSE29609 cohort. Conclusions: UPS is dysregulated in ccRCC. UPS related genes have significant prognostic value in ccRCC. Models constructed with UPSs are effective and applicable. An abnormal ubiquitin proteasome system should play an important role in ccRCC and be worthy of further study.

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“…The indirect inhibition strategy involves targeting HIF regulators (including some 2OGDDs) or HIF-mediated transcriptional responses. We have recently published on the therapeutic potential of targeting USP37, a deubiquitinase which reverses the degradation process of HIF-2α in ccRCC [ 216 ]. Depletion of USP37 impairs ccRCC growth in 2D and 3D growth assays and in vivo kidney tumorigenesis and lung metastasis [ 216 ]; therefore, inhibiting USP37 could be a viable therapeutic approach in VHL-deficient or HIF-2α-dependent tumors.…”

Section: From Mechanisms To Therapeuticsmentioning

confidence: 99%

“…We have recently published on the therapeutic potential of targeting USP37, a deubiquitinase which reverses the degradation process of HIF-2α in ccRCC [ 216 ]. Depletion of USP37 impairs ccRCC growth in 2D and 3D growth assays and in vivo kidney tumorigenesis and lung metastasis [ 216 ]; therefore, inhibiting USP37 could be a viable therapeutic approach in VHL-deficient or HIF-2α-dependent tumors. In addition, an inhibitor of NF-κB activity, BAY 11-7082, prevented EMT and reversed resistance to gemcitabine in pancreatic cancer cells [ 70 ].…”

Section: From Mechanisms To Therapeuticsmentioning

confidence: 99%

Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

Shi

Liao

Zhang

2021

Cells

Self Cite

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Hypoxia, a common feature of solid tumors, greatly hinders the efficacy of conventional cancer treatments such as chemo-, radio-, and immunotherapy. The depletion of oxygen in proliferating and advanced tumors causes an array of genetic, transcriptional, and metabolic adaptations that promote survival, metastasis, and a clinically malignant phenotype. At the nexus of these interconnected pathways are hypoxia-inducible factors (HIFs) which orchestrate transcriptional responses under hypoxia. The following review summarizes current literature regarding effects of hypoxia on DNA repair, metastasis, epithelial-to-mesenchymal transition, the cancer stem cell phenotype, and therapy resistance. We also discuss mechanisms and pathways, such as HIF signaling, mitochondrial dynamics, exosomes, and the unfolded protein response, that contribute to hypoxia-induced phenotypic changes. Finally, novel therapeutics that target the hypoxic tumor microenvironment or interfere with hypoxia-induced pathways are reviewed.

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USP37 promotes deubiquitination of HIF2α in kidney cancer

Cited by 35 publications

References 32 publications

USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin

USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin

Prognostic Role of the Ubiquitin Proteasome System in Clear Cell Renal Cell Carcinoma: A Bioinformatic Perspective

Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

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