GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility

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. [Display omitted] •GAGE is expressed at higher levels in radio-resistant cervical cancer•Only the GAGE12 protein variant contributes to the resistant phenotype•GAGE12 is localized to the chromatin via its interaction with synemin (SYNM)•Chromatin-bound GAGE12 mediates HDAC1/2-ACTB association to inhibit H3K56 deacetylation The cancer/testis (CT) antigen GAGE is expressed in several cancers. However, the molecular intricacies of how GAGE functions within the cell remains poorly defined. Nin et al. describe a role for GAGE in altering chromatin accessibility, leading to more efficient DNA repair, contributing to the radio-resistant phenotype in cervical cancer.