Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation

// Yu Liu 1, * , Duo Li 3, * , Dan Nie 1, * , Shang-Kun Liu 1 , Fang Qiu 1 , Mei-Tong Liu 1 , Yuan-Yuan Li 1 , Jia-Xin Wang 1 , Yan-Xin Liu 1 , Chang-Jiang Dong 1 , Di Wu 1 , Wei Tian 1 , Jia Yang 1 , Wei Mu 1 , Jia-Tong Li 1 , Dan Zhao 2 , Xiao-Feng Wang 3 , Wen-Feng Chu 1 and Bao-Feng Yang 1 1 Department of Pharmacology, The State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University at Harbin, Heilongjiang 150081, P. R. China 2 Department of Clinical Pharmacy, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, The 2nd Affiliated Hospital, Harbin Medical University at Harbin, Heilongjiang 150081, P. R. China 3 Department of Oral and Maxillofacial Surgery, The 2nd Affiliated Hospital, Harbin Medical University at Harbin, Heilongjiang 150081, P. R. China * These authors contributed equally to this work Correspondence to: Wen-Feng Chu, email: cwf76928@aliyun.com Bao-Feng Yang, email: yangbf@ems.hrbmu.edu.cn Keywords: cardiotoxicity, human ether-a-go-go-related gene, transforming growth factor β1, PML nuclear body, SUMOylation Received: October 12, 2016      Accepted: April 17, 2017      Published: May 02, 2017 ABSTRACT The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II. Conversely, knockdown of RNF4 led to a remarkable increase in PML SUMOylation and the function of PML-NBs, further promoting ATO- or Ang II-induced HERG protein downregulation. Mechanistically, an increase in PML SUMOylation by ATO or Ang II dramatically enhanced the formation of PML and Pin1 complexes in PML-NBs, leading to the upregulation of TGF-β1 protein, eventually inhibiting HERG expression through activation of protein kinase A. The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.