YC-1 inhibits proliferation of breast cancer cells by downregulating EZH2 expression via activation of c-Cbl and ERK

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Title:	YC-1 inhibits proliferation of breast cancer cells by downregulating EZH2 expression via activation of c-Cbl and ERK
Authors:	余永倫;Su, KJ;Su, KJ;Hsieh, MJ;Hsieh, MJ;Wang, SS;Wang, SS;Wang, PH;Wang, PH;Weng, WC;Weng, WC;Yang, SF;Yang, SF
Contributors:	生物科技學系
Date:	2014-04
Issue Date:	2014-06-04 02:22:16 (UTC+0)
Abstract:	BACKGROUND AND PURPOSE: YC-1 exhibits potent anticancer activity via numerous actions in many cancer cell lines. Hence, we investigated the in vivo antitumour efficacy of YC-1 in an MDA-MB-468 xenograft model and elucidated the mechanism of down-regulation of enhancer of zeste homology 2 (EZH2) by YC-1 in breast cancer cells. EXPERIMENTAL APPROACH: In YC-1-treated breast cancer cells and tumour specimens from YC-1-treated MDA-MB-468 xenografts, EZH2 expression was analysed by Western blotting. Pharmacological inhibitors and short hairpin RNA-mediated knockdown were applied to identify possible signalling pathways involved in EZH2 down-regulation by YC-1. KEY RESULTS: YC-1 reduced the viability of breast cancer cells and tumour growth in MDA-MB-468 xenografts. In breast cancer cells, YC-1 down-regulated EZH2 expression in a concentration- and time-dependent manner. Depletion of EZH2 reduced the proliferation and susceptibility of breast cancer cells to YC-1-induced apoptosis. EZH2 expression was suppressed in tumour specimens from YC-1-treated MDA-MB-468 xenograft mice. YC-1 enhanced both the degradation rate and ubiquitination of EZH2. The down-regulation of EZH2 by YC-1 was associated with activation of PKA and Src-Raf-ERK-mediated signalling pathways. Furthermore, depletion of Casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase, abolished YC-1-induced apoptosis and suppression of EZH2. YC-1 rapidly activated c-Cbl to induce signalling associated with ERK and EZH2. CONCLUSION AND IMPLICATIONS: We discovered that YC-1 induces apoptosis and inhibits tumour growth of breast cancer cells via down-regulation of EZH2 by activating c-Cbl and ERK. These data suggest that YC-1 is a potential anticancer drug candidate for triple-negative breast cancer. © 2014 The British Pharmacological Society.
Relation:	BRITISH JOURNAL OF PHARMACOLOGY;171(17):4010-25.
Appears in Collections:	[Department of Biotechnology] Journal Article

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