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

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.

• Authors: Ling-Chu Chang, Hui-Yi Lin, Meng-Tung Tsai, Ruey-Hwang Chou, Fang-Yu Lee, Che-Ming Teng, Min-Tsang Hsieh, Hsin-Yi Hung, Li-Jiau Huang, Yung-Luen Yu, Sheng-Chu Kuo
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 17 Pg. 4010-25 (Sep 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24697523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Antineoplastic Agents
• Indazoles
• 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2
• Proto-Oncogene Proteins c-cbl
• Extracellular Signal-Regulated MAP Kinases
• CBL protein, human

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Enhancer of Zeste Homolog 2 Protein
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Indazoles (chemistry, pharmacology)
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Polycomb Repressive Complex 2 (biosynthesis, deficiency, genetics)
• Proto-Oncogene Proteins c-cbl (metabolism)
• Structure-Activity Relationship