Epidermal squamous cell carcinoma (SCC) is a common and highly invasive form of cancer.,SCC arises due to ultraviolet light exposure and is associated with increased expression of pro-cancer genes and reduced expression of cancer suppressors.,Actin-Like Protein 6A (ACTL6A, BAF53a) is an important protein subunit of the SWI/SNF epigenetic chromatin regulatory complex.,ACTL6A is elevated in cancer cells and has been implicated as a driver of cancer cell proliferation and tumor growth.,In the present study, we show that ACTL6A drives SCC cell proliferation, spheroid formation, invasion and migration, and that these activities are markedly reduced by ACTL6A knockdown.,We further show that ACTL6A expression is associated with reduced levels of the p21Cip1 cyclin-dependent kinase inhibitor and tumor suppressor protein.,Molecular studies show that ACTL6A interacts with p53 DNA response elements in the p21Cip1 gene promoter to suppress p21Cip1 promoter activity and mRNA and protein level.,Additional studies show that an increase in p21Cip1 expression in ACTL6A knockdown cells is required for suppression of the SCC cell phenotype, suggesting that p21Cip1 is a mediator of ACTL6A action.,We further show that this regulation is p53 independent.,These findings suggest that ACTL6A suppresses p21Cip1 promoter activity to reduce p21Cip1 protein as a mechanism to maintain the aggressive epidermal squamous cell carcinoma phenotype.
Pro-apoptotic BCL2 associated X (BAX) is traditionally thought to be regulated by anti-apoptotic BCL-2 family members, like BCL2-like 1 (BCL-XL), at the protein level.,However, the posttranscriptional regulation of BAX is under explored.,In this study, we identified BAX as the novel downstream target of miR-365, which is supported by gain- and loss-of-function studies of onco-miR-365.,Loss of BAX by either RNA interference or highly-expressed miR-365 in cells of cutaneous squamous cell carcinoma (CSCC) enhanced the tumor resistance against apoptosis, while repressing cell proliferation, migration, and invasiveness.,In vivo experiment confirmed that BAX knockdown promotes the growth of CSCC xenografts.,Collectively, our results find a miR-365-BAX axis for alleviating the pro-apoptotic effects of BAX, which promotes CSCC development and may facilitate the generation of novel therapeutic regimens to the clinical treatment of CSCC.