Abstract 19: ACTL6A promotes the progression of prostate cancer by modulating GLI1 expression in the Hedgehog signaling pathway

Abstract The disruption of tissue organization is a major contributing factor to the malignant transformation of glandular epithelium, including prostate glands. Three-dimensional organotypic cultures have facilitated the discovery of molecular mechanisms underlying malignant progression. Using a robotic-assisted MicroWestern Array-based proteomics screening, we identified that the protein abundance level of the chromatin remodeling factor ACTL6A is upregulated in disorganized prostate epithelial organoids. We showed that ACTL6A critically regulates prostate glandular morphogenesis as its overexpression led to glrandular transformation. Consistent with this finding, ACTL6A expression is higher in human prostate cancer compared to normal prostate tissue and is associated with poor clinical prognosis. At the functional level, tthe knockdown of ACTL6A expression in PCa cells attenuated stemness and tumorigenesis in vitro and PCa progression in an orthotopic mouse tumor model. Intriguingly, screening of development-associated signaling pathways identified the Hedgehog (Hh) pathway, whose activity and the target genes were reduced by the loss of ACTL6A expression in PCa cells. Further mechanistic and molecular studies revealed that ACTL6A regulates the protein abundance level of GLI1, the key transcriptional factor in Hh-pathway, PCa cells by disabling its ubiquitin-dependent proteosomal degradation. Our study thus illuminated a novel oncogenic mechanism mediated by the ACTL6A-GLI1-Hh signaling axis in PCa, which may have diagnostic and therapeutic implications. Citation Format: Li-Hsin Cheng, Kelvin K. Tsai. ACTL6A promotes the progression of prostate cancer by modulating GLI1 expression in the Hedgehog signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 19.