ACTL6A promotes repair of cisplatin-induced DNA damage, a new mechanism of platinum resistance in cancer
Menée sur des cellules de cancer de l'ovaire et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel la sous-unité protéique ACTL6A favorise la réparation des dommages causés à l'ADN par le cisplatine
Platinum resistance remains as a major issue in the therapy for many types of cancer. However, the mechanisms of resistance have not been fully elucidated. ACTL6A gene is frequently amplified in several types of cancer such as lung squamous cell carcinoma, ovarian cancer, and esophageal cancer. ACTL6A is a subunit shared by multiple complexes, including SWI/SNF, INO80, and NuA4/TIP60. We unveil a new role for ACTL6A in repairing cisplatin-induced DNA damage, providing a novel mechanism for cisplatin resistance. We also show that the action of ACTL6A in the repair of cisplatin-induced DNA lesions is through the SWI/SNF remodeling complex. Furthermore, we demonstrate that an HDAC inhibitor can abolish cisplatin resistance caused by ACTL6A overexpression.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.All study data are included in the article and supporting information.