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

Cell Rep. 2021 Aug 31;36(9):109621. doi: 10.1016/j.celrep.2021.109621.

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: CT antigens; DNA damage response; DNA repair; GAGE; GAGE12; cancer testis antigens; cervical cancer; chromatin dynamics; radioresistance; radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Antigens, Neoplasm* / genetics
  • Antigens, Neoplasm* / metabolism
  • Chromatin Assembly and Disassembly*
  • Chromatin* / genetics
  • Chromatin* / metabolism
  • DNA Repair
  • Female
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histones* / metabolism
  • Humans
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism
  • Lysine
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Processing, Post-Translational
  • Radiation Tolerance* / genetics
  • Signal Transduction
  • Uterine Cervical Neoplasms* / genetics
  • Uterine Cervical Neoplasms* / metabolism
  • Uterine Cervical Neoplasms* / pathology
  • Uterine Cervical Neoplasms* / radiotherapy
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, Neoplasm
  • Chromatin
  • desmuslin
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histones
  • Intermediate Filament Proteins
  • Lysine
  • GAGE12B protein, human