ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer

Proc Natl Acad Sci U S A. 2021 Jan 19;118(3):e2015808118. doi: 10.1073/pnas.2015808118.


Cisplatin is a mainstay of systemic therapy for a variety of cancers, such as lung cancer, head and neck cancer, and ovarian cancer. However, resistance to cisplatin represents one of the most significant barriers for patient outcome improvement. Actin-like 6A (ACTL6A) is a component of several chromatin remodeling complexes, including SWI/SNF, NuA4/TIP60 histone acetylase, and INO80. Amplification of ACTL6A gene is often seen in lung squamous cell carcinoma, ovarian cancer, and esophageal cancer, but its significance remains to be fully determined. Here we identify ACTL6A overexpression as a novel cause for platinum resistance. High levels of ACTL6A are associated with chemoresistance in several types of human cancer. We show that overexpression of ACTL6A leads to increased repair of cisplatin-DNA adducts and resistance to cisplatin treatment. In contrast, depletion of ACTL6A inhibits the repair of cisplatin-induced DNA lesions, and increases cisplatin sensitivity in cisplatin-resistant ovarian cancer cells. The regulation of repair by ACTL6A is mediated through the SWI/SNF chromatin remodeling complex. Treatment with a histone deacetylase inhibitor can reverse the effect of ACTL6A overexpression on the repair of cisplatin-induced DNA damage and render cancer cells more sensitive to cisplatin treatment in a xenograft mouse model. Taken together, our study uncovers a novel role for ACTL6A in platinum resistance, and provides evidence supporting the feasibility of using HDAC inhibitors for platinum resistant tumors.

Keywords: ACTL6A; DNA repair; SWI/SNF; cisplatin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Actins / genetics*
  • Actins / metabolism
  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / mortality
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • Chromatin / chemistry
  • Chromatin / drug effects
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Cisplatin / therapeutic use
  • DNA Adducts
  • DNA Damage
  • DNA Repair / drug effects*
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lysine Acetyltransferase 5 / genetics
  • Lysine Acetyltransferase 5 / metabolism
  • Mice
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / mortality
  • Panobinostat / therapeutic use
  • Survival Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Xenograft Model Antitumor Assays


  • ACTL6A protein, human
  • Actins
  • Antineoplastic Agents
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA Adducts
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors
  • cisplatin-DNA adduct
  • Panobinostat
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • ATPases Associated with Diverse Cellular Activities
  • INO80 protein, human
  • Cisplatin