ACTL6A suppresses p21Cip1 tumor suppressor expression to maintain an aggressive mesothelioma cancer cell phenotype

Abstract

AbstractMesothelioma 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 p21Cip1 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 p21Cip1 gene promoter and that this is associated with reduced p21Cip1 promoter activity and p21Cip1 mRNA and protein levels. Moreover, ACTL6A suppression of p21Cip1 expression is required for maintenance of the aggressive mesothelioma cancer cell phenotype suggesting that p21Cip1 is a mediator of ACTL6A action. p53, a known inducer of p21Cip1 expression, is involved ACTL6A in regulation of p21Cip1 in some but not all mesothelioma cells. In addition, ACTL6A knockout markedly reduces tumor formation and this is associated with elevated tumor levels of p21Cip1. These findings suggest that ACTL6A suppresses p21Cip1 promoter activity to reduce p21Cip1 protein as a mechanism to maintain the aggressive mesothelioma cell phenotype.