Affiliation: | 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, Republic of Korea Jaesung Seo and Garam Guk equally contributed to this work.;2. Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Republic of Korea;3. 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, Republic of Korea;4. Department of Biomedical Sciences, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea |
Abstract: | The role of histone deacetylase 3 (HDAC3) is to repress the expression of various genes by eliminating acetyl group from histone. Thus, the regulation of HDAC3 activity is essential to maintain cellular homeostasis. In this study, we found that HDAC3 interacts with c-Src kinase. However, the interaction between HDAC3 and c-Src was previously reported, it has still been ambiguous whether c-Src phosphorylates HDAC3 and affects the function of HDAC3. First, we confirmed that HDAC3 directly binds to c-Src, and c-Src identified to interact with C-terminal domain (277–428 a.a.) of HDAC3. c-Src also phosphorylated three tyrosine sites of HDAC3 at tyrosine 325, 328, and 331. Importantly, wild-type c-Src increases HDAC3 activity, but not mutant c-SrcK298M (kinase inactive form). When these tyrosine residues are all substituted for alanine residues, the deacetylase activity of mutant HDAC3 was abolished. In addition, a proliferation of HER2-positive breast cancer cells expressing phosphorylation deficient mutant HDAC3 is decreased in comparison with control cells. Thus, our findings suggested that phosphorylation of HDAC3 by c-Src kinase regulates the HDAC3 activity and the proliferation of breast cancer cells. |