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

 Sung-Min Kwak  ;  Jaesung Seo  ;  Jin-Taek Hwang  ;  Gi-Jun Sung  ;  Ji-Hye Song  ;  Ji-Hoon Jeong  ;  Seung-Hyun Lee  ;  Ho-Geun Yoon  ;  Hyo-Kyoung Choi  ;  Kyung-Chul Choi 
 CELLS, Vol.8(8) : 930, 2019-08 
Journal Title
Issue Date
Breast Neoplasms / metabolism* ; ErbB Receptors / physiology ; HEK293 Cells ; HeLa Cells ; Histone Deacetylases / physiology* ; Humans ; MCF-7 Cells ; Proto-Oncogene Mas ; Proto-Oncogene Proteins pp60(c-src) / physiology* ; Signal Transduction
breast cancer ; c-Src ; EGFR ; HDAC3 ; pY-HDAC3Y328 ; 331 antibody
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.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Lee, Seung Hyun(이승현) ORCID logo https://orcid.org/0000-0001-7549-9430
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