De-acetylation and degradation of HSPA5 is critical for E1A metastasis suppression in breast cancer cells

Abstract

// Yi-Wen Chang 1,* , Hsin-An Chen 2,3,* , Chi-Feng Tseng 1,4 , Chih-Chen Hong 1 , Jui-Ti Ma 1,4 , Mien-Chie Hung 5,6,7,8 , Chih-Hsiung Wu 2,3 , Ming-Te Huang 2,3 and Jen-Liang Su 1,5,6,7 1 National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli Country, Taiwan 2 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 3 Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 4 Graduate Program of Biotechnology in Medicine College of Life Science, National Tsing Hua University, Hsinchu, Taiwan 5 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 6 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan 7 Department of Biotechnology, Asia University, Taichung, Taiwan 8 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * These authors contributed equally to this work Correspondence: Jen-Liang Su , email: // Keywords : acetylation, adenovirus type 5 E1A, HSPA5/GRP78/Bip, metastasis, ubiquitination Received : July 02, 2014 Accepted : September 24, 2014 Published : September 25, 2014 Abstract Elevated expression of heat shock protein 5 (HSPA5) promotes drug resistance and metastasis and is a marker of poor prognosis in breast cancer patients. Adenovirus type 5 E1A gene therapy has demonstrated antitumor efficacy but the mechanisms of metastasis-inhibition are unclear. Here, we report that E1A interacts with p300 histone acetyltransferase (HAT) and blocks p300-mediated HSPA5 acetylation at K353, which in turn promotes HSPA5 ubiquitination by GP78 (E3 ubiquitin ligase) and subsequent proteasome-mediated degradation. Our findings point out the Ying-Yang regulation of two different post-translational modifications (ubiquitination and acetylation) of HSPA5 in tumor metastasis.