GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility
Dawn Sijin Nin, Caryn Wujanto, Tuan Zea Tan, Diana Lim, J Damen, Kuan-Yi Wu, Ziyu Dai, Zheng‐Wei Lee, Shabana Binte Idres, Yiat Horng Leong, Sudhakar Jha, Joseph Ng, Jeffrey Low, Shih‐Chung Chang, David S.P. Tan, Wei Wu, Bok Ai Choo, Lih‐Wen Deng
Abstract
Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.