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MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3? signaling impedes castration-resistant prostate cancer growth.

ABSTRACT: Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both in vitro and in vivo. Integrative database analyses and co-immunoprecipitation assays were performed to elucidate genomic association of MYSM1 and MYSM1-involved biological interaction network in PCa. We observed that MYSM1 were downregulated in CRPC compared to localized prostate tumors. Knockdown of MYSM1 promoted cell proliferation and suppressed senescence of CRPC cells under condition of androgen ablation. MYSM1 downregulation enhanced the tumorigenic ability in nude mice. Integrative bioinformatic analyses of the significantly associated genes with MYSM1 revealed MYSM1-correlated pathways, providing substantial clues as to the role of MYSM1 in PCa. MYSM1 was able to bind to androgen receptor instead of increasing its expression and knockdown of MYSM1 resulted in activation of Akt/c-Raf/GSK-3? signaling. Together, our findings indicate that MYSM1 is pivotal in CRPC pathogenesis and may be established as a potential target for future treatment.

SUBMITTER: Sun J

PROVIDER: S-EPMC6914400 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3β signaling impedes castration-resistant prostate cancer growth.

Sun Jinbo J Hu Xiangnan X Gao Yongheng Y Tang Qisheng Q Zhao Zhining Z Xi Wenjin W Yang Fan F Zhang Wei W Song Yue Y Song Bin B Wang Tao T Wang He H

Aging 20191124 22

Epigenetic alterations that lead to dysregulated gene expression in the progression of castration-resistant prostate cancer (CRPC) remain elusive. Here, we investigated the role of histone deubiquitinase MYSM1 in the pathogenesis of prostate cancer (PCa). Tissues and public datasets of PCa were evaluated for MYSM1 levels. We explored the effects of MYSM1 on cell proliferation, senescence and viability both <i>in vitro</i> and <i>in vivo</i>. Integrative database analyses and co-immunoprecipitati ...[more]

PMID: 31761786

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Project description:BackgroundMetastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial-mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified.MethodsThe expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting.ResultsCHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002.ConclusionThese results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

Dataset Information

MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3? signaling impedes castration-resistant prostate cancer growth.

Publications

MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3β signaling impedes castration-resistant prostate cancer growth.

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