ACTL6A suppresses p21(Cip1) tumor suppressor expression to maintain an aggressive mesothelioma cancer cell phenotype

Mesothelioma is a poor prognosis cancer of the mesothelial lining that develops in response to exposure to various agents including asbestos. Actin-Like Protein 6A (ACTL6A, BAF53a) is a SWI/SNF regulatory complex protein that is elevated in cancer cells and has been implicated as a driver of cancer cell survival and tumor formation. In the present study, we show that ACTL6A drives mesothelioma cancer cell proliferation, spheroid formation, invasion, and migration, and that these activities are markedly attenuated by ACTL6A knockdown. ACTL6A expression reduces the levels of the p21(Cip1) cyclin-dependent kinase inhibitor and tumor suppressor protein. DNA binding studies show that ACTL6A interacts with Sp1 and p53 binding DNA response elements in the p21(Cip1) gene promoter and that this is associated with reduced p21(Cip1) promoter activity and p21(Cip1) mRNA and protein levels. Moreover, ACTL6A suppression of p21(Cip1) expression is required for maintenance of the aggressive mesothelioma cancer cell phenotype suggesting that p21(Cip1) is a mediator of ACTL6A action. p53, a known inducer of p21(Cip1) expression, is involved ACTL6A in regulation of p21(Cip1) in some but not all mesothelioma cells. In addition, ACTL6A knockout markedly reduces tumor formation and this is associated with elevated tumor levels of p21(Cip1). These findings suggest that ACTL6A suppresses p21(Cip1) promoter activity to reduce p21(Cip1) protein as a mechanism to maintain the aggressive mesothelioma cell phenotype.