YC-1 inhibits proliferation of breast cancer cells by down-regulating EZH2 expression via activation of c-Cbl and ERK
Journal
British Journal of Pharmacology
Journal Volume
171
Journal Issue
17
Pages
4010-4025
Date Issued
2014
Author(s)
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.
SDGs
Other Subjects
antineoplastic agent; Cbl protein; cyclic AMP dependent protein kinase; lificiguat; lificiguat succinate; mitogen activated protein kinase; protein tyrosine kinase; Raf protein; transcription factor EZH2; unclassified drug; 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; antineoplastic agent; Cbl protein; CBL protein, human; EZH2 protein, human; indazole derivative; mitogen activated protein kinase; polycomb repressive complex 2; animal experiment; animal model; animal tissue; apoptosis; article; breast cancer; breast cancer cell line; cancer cell; cancer inhibition; cell proliferation; cell viability; concentration response; controlled study; dose response; down regulation; drug efficacy; drug mechanism; enzyme activation; female; IC 50; in vivo study; mouse; nonhuman; priority journal; protein degradation; protein depletion; protein expression; signal transduction; tumor growth; tumor xenograft; ubiquitination; animal; biosynthesis; Breast Neoplasms; cell proliferation; cell survival; chemistry; deficiency; drug effects; drug screening; gene expression regulation; genetics; human; Mammary Neoplasms, Experimental; metabolism; pathology; structure activity relation; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Drug Screening Assays, Antitumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Indazoles; Mammary Neoplasms, Experimental; Mice; Polycomb Repressive Complex 2; Proto-Oncogene Proteins c-cbl; Structure-Activity Relationship
Type
journal article