GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility
Journal
Cell Reports
Journal Volume
36
Journal Issue
9
Pages
Article number 109621
Date Issued
2021-08-31
Author(s)
Nin, Dawn Sijin et al.
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.
Subjects
cancer testis antigens
cervical cancer
chromatin dynamics
CT antigens
DNA damage response
DNA repair
GAGE
GAGE12
radioresistance
radiotherapy
SDGs
Publisher
Elsevier B.V.
Type
journal article