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USP7 stabilizes EZH2 and enhances cancer malignant progression.

ABSTRACT: EZH2, a histone methylase, plays a critical role in the tumor progression via regulation of progenitor genes. However, the detailed molecular mechanism of EZH2 in cancer malignant progression remains unknown. Therefore, we aimed to investigate how EZH2 is regulated in human cancer. We used numerous approaches, including Co-immunoprecipitation (Co-IP), Transfection, RT-PCR, Western blotting, Transwell assays, and animal studies, to determine the deubiquitination mechanism of EZH2 in cancer cells. We demonstrated that USP7 regulated EZH2 in human cancer cells and in vivo in mouse models. Overexpression of USP7 promoted the expression of EZH2 protein, but overexpression of a USP7 mutant did not change the EZH2 level. Consistently, knockdown of USP7 resulted in a striking decrease in EZH2 protein levels in human cancer cells. Functionally, USP7 overexpression promoted cell growth and invasion via deubiquitination of EZH2. Consistently, downregulation of USP7 inhibited cell migration and invasion in cancer. More importantly, knockdown of USP7 inhibited tumor growth, while USP7 overexpression exhibited opposed effect in mice. Our results indicate that USP7 regulates EZH2 via its deubiquitination and stabilization. The USP7/EZH2 axis could present a new promising therapeutic target for cancer patients.

SUBMITTER: Zheng N

PROVIDER: S-EPMC7017725 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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USP7 stabilizes EZH2 and enhances cancer malignant progression.

Zheng Nana N Chu Man M Lin Min M He Youhua Y Wang Zhiwei Z

American journal of cancer research 20200101 1

EZH2, a histone methylase, plays a critical role in the tumor progression via regulation of progenitor genes. However, the detailed molecular mechanism of EZH2 in cancer malignant progression remains unknown. Therefore, we aimed to investigate how EZH2 is regulated in human cancer. We used numerous approaches, including Co-immunoprecipitation (Co-IP), Transfection, RT-PCR, Western blotting, Transwell assays, and animal studies, to determine the deubiquitination mechanism of EZH2 in cancer cells. ...[more]

PMID: 32064169

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Project description:BackgroundInvasion and metastasis are the main causes of unfavourable prognosis in patients diagnosed with bladder cancer. The efficacy of immunotherapy in bladder cancer remains suboptimal due to the presence of an immunosuppressive microenvironment. The novel protein family with sequence similarity 171B (FAM171B) has been identified, but its precise role and mechanism in bladder cancer remain unclear.MethodsIn this study, we conducted an analysis to investigate the associations between FAM171B expression and the prognosis and clinicopathological stage of bladder cancer. To this end, we utilized RNA sequencing data from the TCGA and GEO databases, as well as tumor tissue specimens obtained from our clinical centre. RNA sequencing analysis allowed us to examine the biological function of FAM171B at the transcriptional level in bladder cancer cells. Additionally, we used immunoprecipitation and mass spectrometry to identify the protein that interacts with FAM171B in bladder cancer cells. The effects of FAM171B on modulating tumor-associated macrophages (TAMs) and vimentin-mediated tumor progression, as well as the underlying mechanisms, were clarified by phalloidin staining, immunofluorescence staining, ELISA, RNA immunoprecipitation, flow cytometry and a bladder cancer graft model.ResultsFAM171B expression exhibits strong positive correlation with poor survival outcomes and advanced clinicopathological stages in patients with bladder cancer. FAM171B significantly promoted bladder cancer growth and metastasis, accompanied by TAM accumulation in the microenvironment, in vivo and in vitro. Through studies of the molecular mechanism, we found that FAM171B contributes to tumor progression by stabilizing vimentin in the cytoplasm. Additionally, our research revealed that FAM171B enhances the splicing of CCL2 mRNA by interacting with heterogeneous nuclear ribonucleoprotein U (HNRNPU), ultimately leading to increased recruitment and M2 polarization of TAMs.ConclusionsIn this study, we identified FAM171B as a potent factor that promotes the progression of bladder cancer. These findings establish a solid theoretical foundation for considering FAM171B as a potential diagnostic and therapeutic biomarker for bladder cancer.

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USP7 stabilizes EZH2 and enhances cancer malignant progression.

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USP7 stabilizes EZH2 and enhances cancer malignant progression.

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