ACTL6A is a novel oncogene and prognostic biomarker for prostate cancer

Abstract

Abstract ACTL6A (Actin-like 6A protein) is a member of ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes encoding a family of actin-related proteins. Using 3D culture and Micro-Western Array analysis targeting for epigenetic regulatory proteins, we discovered that ACTL6A plays essential role in regulation of the prostate acinar morphogenesis, a differentiation procedure. Expression level of ACTL6A protein decreases dramatically during prostate acinar morphogenesis, suggesting that ACTL6A is a potential oncogene in prostate cancer (PCa). We analyzed Oncomine online database and found that ACTL6A is higher in prostate cancer vs. adjacent normal prostate tissues, while ACTL6A protein level is even higher in metastatic PCa. High ACTL6A gene expression level in prostate tumors correlates to worse PCa patient survival outcome. We knocked down ACTL6A in PC-3 PCa cells, and the reduction of ACTL6A suppressed proliferation, migration, and invasion of PC-3 cells. Knockdown of ACTL6A also reduced population of CD44+ and ALDH enzyme activity-positive PCa cells, which represents the population of cancer stem cell (CSC) in PCa. Decrease of ACTL6A reduced expression of a few oncogenic long non-coding RNA, including HIFCAR, MALAT1, and PCAT-1. Seahorse mito-stress and glycol-stress analysis revealed that knockdown of ACTL6A suppressed OCR and ECAR of mitochondria in PCa cells. ACTL6A knockdown up-regulates expression of glycolysis-related genes, suggesting that ACTL6A regulate cancer metabolism. Our study suggested that ACTL6A regulates expression and activity of YAP and c-Myc, which in turn regulates stemness factors Nanog and Sox2, thus enhances the cancer stemness of PCa cells. ACTL6A also regulates mitochondrial function and metabolic genes PKM2, LDHA, GLS1, partially through c-Myc, therefore ACTL6A causes metabolism rewiring in PCa. All these regulations contribute to the metastasis of PCa. In conclusion, ACTL6A is a novel oncogene and prognostic biomarker for PCa.