Delphinidin induces apoptosis via cleaved HDAC3-mediated p53 acetylation and oligomerization in prostate cancer cells

Abstract

// Mi-Hyeon Jeong 1, 4, * , Hyeonseok Ko 5, * , Hyelin Jeon 1, 2 , Gi-Jun Sung 1, 2 , Soo-Yeon Park 4 , Woo Jin Jun 6 , Yoo-Hyun Lee 7 , Jeongmin Lee 8 , Sang-wook Lee 9 , Ho-Geun Yoon 4 , Kyung-Chul Choi 1, 2, 3 1 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea 3 Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, South Korea 4 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, Korea 5 Laboratory of Molecular Oncology, Cheil General Hospital & Women’s Healthcare Center, Dankook University College of Medicine, Seoul, South Korea 6 Department of Food and Nutrition, Chonnam National University, Gwangju, South Korea 7 Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea 8 Department of Medical Nutrition, Kyung Hee University, Yongin-si, Kyunggi-do, South Korea 9 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea * M.H. Jeong and H. Ko are co-first authors and contributed equally to this work Correspondence to: Kyung-Chul Choi, email: choikc75@amc.seoul.kr Ho-Geun Yoon, email: yhgeun@yuhs.ac Keywords: delphinidin, p53, acetylation, HDAC3, apoptosis Received: September 30, 2015     Accepted: June 04, 2016     Published: July 22, 2016 ABSTRACT Delphinidin is a major anthocyanidin compound found in various fruits. It has anti-inflammatory, anti-oxidant, and various other biological activities. In this study, we identified the epigenetic modulators that mediate the apoptotic effect of delphinidin in human prostate cancer cells. We found that treatment of LNCaP cells (a p53 wild-type, human prostate cancer cell line) with delphinidin increased caspase-3, -7, and -8 activity, whereas it decreased histone deacetylase activity. Among class I HDACs, the activity of HDAC3 was specifically inhibited by delphinidin. Moreover, the induction of apoptosis by delphinidin was dependent on caspase-mediated cleavage of HDAC3, which results in the acetylation and stabilization of p53. We also observed that delphinidin potently upregulated pro-apoptotic genes that are positively regulated by p53, and downregulated various anti-apoptotic genes. Taken together, these results show that delphinidin induces p53-mediated apoptosis by suppressing HDAC activity and activating p53 acetylation in human prostate cancer LNCaP cells. Therefore, delphinidin may be useful in the prevention of prostate cancer.