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

• Published in: Oncotarget Vol. 5; no. 21; pp. 10558 - 10570
• Main Authors: Chang, Yi-Wen, Chen, Hsin-An, Tseng, Chi-Feng, Hong, Chih-Chen, Ma, Jui-Ti, Hung, Mien-Chie, Wu, Chih-Hsiung, Huang, Ming-Te, Su, Jen-Liang
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.11.2014
• Subjects: Acetylation; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Animals; Apoptosis; Blotting, Western; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cell Movement; Cell Proliferation; E1A-Associated p300 Protein - genetics; E1A-Associated p300 Protein - metabolism; Female; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Immunoenzyme Techniques; Immunoprecipitation; Lung Neoplasms - metabolism; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mice; Mice, SCID; Protein Binding; Protein Processing, Post-Translational; Real-Time Polymerase Chain Reaction; Research Paper; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tumor Cells, Cultured; Ubiquitination; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2510

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.