Abstract LB214: Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype

Abstract

Abstract Mesothelioma is a fatal asbestos-caused cancer of the mesothelial cells that arises in the pleural and peritoneal cavities in response to asbestos exposure. ACTL6A is an important protein subunit of the SWI/SNF epigenetic regulatory complex but also has independent pro-cancer actions. It is frequently overexpressed in cancer and drives the malignant phenotype; however, it has not been studied in mesothelioma. In the present report, we show that ACTL6A drives mesothelioma cell proliferation, invasion and migration, and that these activities are markedly reduced in ACTL6A knockdown/knockout cells. Moreover, ACTL6A loss is associated with a significant increase in level of the p21Cip1 cyclin-dependent kinase inhibitor. ACTL6A binding to the proximal Sp1 and distal p53 sites on the p21Cip1 gene promoter is associated with reduced p21Cip1 promoter activity, and mRNA and protein level. Similar regulation was observed in cells derived from plural and peritoneal mesothelioma. Moreover, inhibiting the p21Cip1 increase in ACTL6A knockout cells reverses the reduction in cancer phenotype, suggesting the p21Cip1 is an authentic downstream mediator of ACTL6A action. These studies suggest that ACTL6A suppression of p21Cip1 expression contributes to the mesothelioma cell aggressive cancer phenotype and that inhibition of ACTL6A function may be a suitable mesothelioma cancer treatment strategy. Citation Format: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Joseph Friedburg, Richard L. Eckert. Actin-Like Protein 6A (ACTL6A) Suppresses p21Cip1 Expression to Maintain an Aggressive Mesothelioma Phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB214.