biostudies-literatureKaushal JBUnited States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research ProgramsUnited States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)1007-1023https://www.ebi.ac.uk/biostudies/studies/S-EPMC11976299biostudies-literatureUnknown44(15)The functional activation of the androgen receptor (AR) and its interplay with the aberrant Hh/Gli cascade are pivotal in the progression of castration-resistant prostate cancer (CRPC) and resistance to AR-targeted therapies. Our study unveiled a novel role of the truncated form of Gli (t-Gli3) in advancing CRPC. Investigation into Gli3 regulation revealed a Smo-independent mechanism for its activation. Despite lacking a transactivation domain, t-Gli3 relies on androgen receptor variant 7 (AR-V7) for its action. Mechanistically, Gsk3β activation led to the t-Gli3 generation, and inhibition of Gsk3β supported the accumulation of full-length Gli3 expression through a non-canonical mechanism. Knockdown of Gsk3β (Gsk3β KD) reduces CRPC cell proliferation, induces apoptosis via mitochondrial frOncogeneOncogenic potential of truncated-Gli3 via the Gsk3β/Gli3/AR-V7 axis in castration-resistant prostate cancer.PMC11976299DOD W81XWH-18-1-0308DOD W81XWH-21-1-0340W81XWH-21-1-0640Parte SKaushal JBRaut PSharma GSeshacharyulu PLele SMBatra SKHalder SSiddiqui JAAlsafwani ZWAbdullah KMfalseOncogenic potential of truncated-Gli3 via the Gsk3β/Gli3/AR-V7 axis in castration-resistant prostate cancer.The functional activation of the androgen receptor (AR) and its interplay with the aberrant Hh/Gli cascade are pivotal in the progression of castration-resistant prostate cancer (CRPC) and resistance to AR-targeted therapies. Our study unveiled a novel role of the truncated form of Gli (t-Gli3) in advancing CRPC. Investigation into Gli3 regulation revealed a Smo-independent mechanism for its activation. Despite lacking a transactivation domain, t-Gli3 relies on androgen receptor variant 7 (AR-V7) for its action. Mechanistically, Gsk3β activation led to the t-Gli3 generation, and inhibition of Gsk3β supported the accumulation of full-length Gli3 expression through a non-canonical mechanism. Knockdown of Gsk3β (Gsk3β KD) reduces CRPC cell proliferation, induces apoptosis via mitochondrial fr2025-01-01T00:00:00Z2025 Apr2025-07-05T03:04:32.151Z2025-07-05T03:04:32.151ZS-EPMC119762993982109910.1038/s41388-024-03266-z