EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Cells

Ho-Geun Yoon¹  Seung-Hyun Lee¹  Jaesung Seo¹  Ji-Hoon Jeong²  Ji-Hye Song²  Gi-Jun Sung²  Sung-Min Kwak²  Kyung-Chul Choi²  Hyo-Kyoung Choi³  Jin-Taek Hwang³ 

[1] Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Plus Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea;Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul 05505, Korea;Korea Food Research Institute, Wanju-gun 55365, Korea;

关键词: breast cancer;    c-Src;    EGFR;    HDAC3;    pY-HDAC3^Y328/331 antibody;   

DOI  :  10.3390/cells8080930

来源: DOAJ

【 摘 要 】

Breast cancer is one of the leading causes of morbidity and mortality among women. Epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src (c-Src) are critical components of the signaling pathways that are associated with breast cancer. However, the regulatory mechanism of histone deacetylase 3 (HDAC3) in these pathways remains unclear. Using the Net Phos 3.1 program for the analysis of kinase consensus motifs, we found two c-Src-mediated putative phosphorylation sites, tyrosine (Tyr, Y)-328 and Y331 on HDAC3, and generated a phospho-specific HDAC3 antibody against these sites. c-Src-mediated phosphorylation was observed in the cells expressing wild-type HDAC3 (HDAC3^WT), but not in cells overexpressing phosphorylation-defective HDAC3 (HDAC3^Y328/331A). Phosphorylated HDAC3 showed relatively higher deacetylase activity, and PP2, which is a c-Src inhibitor, blocked HDAC3 phosphorylation and reduced its enzymatic activity. EGF treatment resulted in HDAC3 phosphorylation in both MDA-MB-231 and EGFR-overexpressing MCF7 (MCF7-EGFR) cells, but not in MCF7 cells. Total internal reflection fluorescence analysis showed that HDAC3 was recruited to the plasma membrane following EGF stimulation. HDAC3 inhibition with either c-Src knockdown or PP2 treatment significantly ameliorated the invasiveness of breast cancer cells. Altogether, our findings reveal an EGF signaling cascade involving EGFR, c-Src, and HDAC3 in breast cancer cells.

【 授权许可】

Unknown