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Biological significance of EZH2 in uterine cancer

ABSTRACT: Change of gene expression profile by EZH2 silencing EZH2 is overexpressed in a number of malignancies, and is an attractive target for cancer treatment. The overexpression of EZH2 was significantly associated with disease free survival and overall survival of patients with ovarian cancer. EZH2 silencing resulted in decreased cell viability and invasion ability, and increased apoptosis. EZH2 silencing significantly enhanced cytotoxicity of paclitaxel, docetaxel and cisplatin in Hec-1A and Ishikawa cells. EZH2 silencing using siRNA incorporated into chitosan nanoparticles (siRNA/CH) resulted in significant inhibition of tumor growth compared to control siRNA/CH. Moreover, EZH2 siRNA/CH in combination with taxanes showed robust anti-tumor effects compared to monotherapy groups. These effects were associated with decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Genomic analyses revealed that EZH2 gene silencing resulted in decreased expression of many genes associated with tumor growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115010 | GEO | 2019/05/01

REPOSITORIES: GEO

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Project description:Diaphanous-related formin-3 (DIAPH3), a cytoskeletal regulator of the formin family, is lost at high frequency in metastatic breast and prostate cancers and has characteristics of a non-canonical metastasis suppressor. We previously demonstrated that DIAPH3 silencing evokes transition to an “amoeboid” phenotype, characterized by rapid motility, RhoA/ROCK and MEK/ERK pathway activation, dynamic membrane blebbing, and increased shedding of microvesicles. Here we report that low DIAPH3 mRNA expression correlates with reduced survival in multiple cancer patient cohorts. In line with induction of amoeboid behavior, traction force microscopy (TFM) revealed that polarized force generation, contractility, and response to substrate stiffness are reduced by DIAPH3 loss. Proteomic analyses revealed that DIAPH3 precipitates with tubulins, and reciprocal co-immunoprecipitation analyses revealed greater binding of DIAPH3 to MT polymers than soluble tubulin. DIAPH3 also bound to acetylated-tubulin (Ac-tubulin), suggesting association with a stable MT population. DIAPH3 silencing reduced Ac-tubulin and increased the cellular content of dynamic MT, as indicated by TFM and live cell imaging. DIAPH3 silencing also increased responsiveness to MT-disrupting agents. Treatment with the taxanes paclitaxel and docetaxel, and the non-taxane epothilone B, induced a greater change in Ac-tubulin when cells lacked DIAPH3. Intracellular accumulation of Oregon Green 488-paclitaxel was also increased by DIAPH3 loss, and accordingly, DIAPH3 silencing enhanced cytotoxicity by paclitaxel, docetaxel, or epothilone B. Gene expression profiles of breast cancer patients treated with chemotherapeutic regimens containing taxanes revealed an association of low DIAPH3 expression with improved relapse-free survival. Collectively, these results suggest that regulation of MT stability/dynamics by DIAPH3 enhances amoeboid tumor cell susceptibility to microtubule poisons. These findings have potential therapeutic implications.

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Biological significance of EZH2 in uterine cancer

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