GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility.
Animals
Female
Humans
Acetylation
Antigens, Neoplasm
/ genetics
Chromatin
/ genetics
Chromatin Assembly and Disassembly
DNA Repair
Gene Expression Regulation, Neoplastic
HeLa Cells
Histone Deacetylase 1
/ genetics
Histone Deacetylase 2
/ genetics
Histones
/ metabolism
Intermediate Filament Proteins
/ genetics
Lysine
Mice, Inbred BALB C
Mice, Nude
Protein Processing, Post-Translational
Radiation Tolerance
/ genetics
Signal Transduction
Uterine Cervical Neoplasms
/ genetics
Xenograft Model Antitumor Assays
CT antigens
DNA damage response
DNA repair
GAGE
GAGE12
cancer testis antigens
cervical cancer
chromatin dynamics
radioresistance
radiotherapy
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 08 2021
31 08 2021
Historique:
received:
08
09
2020
revised:
03
06
2021
accepted:
05
08
2021
entrez:
1
9
2021
pubmed:
2
9
2021
medline:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34469741
pii: S2211-1247(21)01059-7
doi: 10.1016/j.celrep.2021.109621
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
Chromatin
0
desmuslin
0
HDAC1 protein, human
EC 3.5.1.98
HDAC2 protein, human
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
Histone Deacetylase 2
EC 3.5.1.98
Histones
0
Intermediate Filament Proteins
0
Lysine
K3Z4F929H6
GAGE12B protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109621Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.