GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility
Nin, Dawn Sijin Wujanto, Caryn Tan, Tuan Zea Lim, Diana Damen, J Mirjam A Wu, Kuan-Yi Dai, Ziyu Melvin Lee, Zheng-Wei Idres, Shabana Binte Leong, Yiat Horng
Wujanto, Caryn
Damen, J Mirjam A
Wu, Kuan-Yi
Leong, Yiat Horng
Citations
Altmetric:
Alternative Title
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.
Keywords
Science & Technology, Life Sciences & Biomedicine, Cell Biology, LYSINE 56 ACETYLATION, DNA-DAMAGE RESPONSE, HISTONE H3, CANCER/TESTIS ANTIGENS, PROSTATE CARCINOMA, TUMOR-ANTIGENS, NUCLEAR ACTIN, RADIATION, GENES, EXPRESSION
Source Title
CELL REPORTS
Publisher
CELL PRESS
Series/Report No.
Collections
Rights
Date
2021-08-31
DOI
10.1016/j.celrep.2021.109621
Type
Article