TNIK swaths AR to WNT pathway and drives Castration-Resistant Prostate Cancer

Abstract

Background: The development of CRPCa was driven by complex genetic and epigenetic mechanisms that remained poorly understood. TNIK (Traf2 and Nck-interacting kinase) has been reported to be a serine/threonine kinase and associated with tumor cell proliferation or unfavorable cancer behavior. The present study was conducted to investigate the TNIK gene expressions in CRPCa. Methods: Using a microarray approach, we identified higher expression of TNIK in CRPCa. The interaction between AR and H3K27me3 upon TNIK depression was determined through molecular and cell biological methods. Co-immunoprecipitations assays were Performed to confirm that TNIK interacted and phosphorylated with β-catenin in CRPCa cell. Results: Specifically we found AR repressed TNIK gene transcription via forming complex with H3K27me3. TNIK was recruited to promote transcription of Wnt target genes in a β-catenin-dependent manner in C4-2 cells. In vitro binding showed that TNIK directly band and phosphorylated β-catenin. Depletion or mutant of TNIK kinase abrogated β-catenin transcription, highlighting the essential function of TNIK kinase activity in Wnt target gene activation. Conclusions: Our findings revealed a regulatory role of AR in TNIK repressor, TNIK interacted with β-catenin and phosphorylated activaing Wnt pathway to promote CRPCa progression. TNIK may present an attractive candidate for drug targeting in CRPCa.