TNIK drives castration-resistant prostate cancer via phosphorylating EGFR
Jianing Guo,
Jiaming Liang,
Youzhi Wang,
Tao Guo,
Yihao Liao,
Boqiang Zhong,
Shuyue Guo,
Qian Cao,
Junbo Li,
Amilcar Flores-Morales,
Yuanjie Niu,
Ning Jiang
Affiliations
Jianing Guo
Department of Pathology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Jiaming Liang
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Youzhi Wang
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Tao Guo
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Yihao Liao
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Boqiang Zhong
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Shuyue Guo
Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300211, China
Qian Cao
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Junbo Li
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Amilcar Flores-Morales
Department of Drug Design and Pharmacology, Københavns Universitet, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Yuanjie Niu
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China
Ning Jiang
Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China; Corresponding author
Summary: The development of castration-resistant prostate cancer (CRPC) is driven by intricate genetic and epigenetic mechanisms. Traf2- and Nck-interacting kinase (TNIK) has been reported as a serine/threonine kinase associated with tumor cell proliferation or unfavorable cancer behavior. The microarray approach revealed a substantial upregulation of TNIK expression levels, enabling us to investigate the functional behaviors of the TNIK gene in CRPC. Specifically, we discovered that AR suppresses TNIK gene transcription in LNCaP and C4-2 cells by forming a complex with H3K27me3. Following the reduction of AR levels induced by androgen deprivation therapy (ADT), TNIK is recruited to activate EGFR signaling through phosphorylation in C4-2 cells, thereby promoting CRPC progression. Our findings unveil a regulatory role of AR as a repressor for TNIK while also highlighting how TNIK activates the EGFR pathway via phosphorylation to drive CRPC progression. Consequently, targeting TNIK may represent an appealing therapeutic strategy for CRPC.
