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

doi:10.1016/j.isci.2023.108713

TNIK drives castration-resistant prostate cancer via phosphorylating EGFR

iScience. 2023 Dec 12;27(1):108713. doi: 10.1016/j.isci.2023.108713. eCollection 2024 Jan 19.

Authors

Affiliations

¹ Department of Pathology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
² Department of Urology, Tianjin Institute of Urology. The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
³ 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.
⁴ Department of Drug Design and Pharmacology, Københavns Universitet, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

Abstract

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.

Keywords: Biochemistry; Cancer; Molecular biology.