Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer

Abstract

Purpose: Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. Experimental Design: We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models. Results: Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through ARand AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy. Conclusions: These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.

Increased expression of KPNA2 predicts unfavorable prognosis in ovarian cancer patients, possibly by targeting KIF4A signaling

“…Kinesin family member 4A (KIF4A) is a highly related gene (Fig. 6 a); it promoted progression in various tumor tissues by regulating chromosome segregation machinery in mediating spindle organization and cytokinesis [ 2 , 5 , 32 ]. A regression analysis using cBioportal showed that KPNA2 and KIF4A levels are highly correlated (Pearson’s correlation = 0.69; Spearman’s correlation = 0.69) (Fig.…”

“…By mining co-expression and correlation analysis data, we demonstrated that KPNA2 and KIF4A were both overexpressed in ovarian carcinoma. KIF4A, a member of the kinesin superfamily (KIFs), is associated with multiple cellular activities, particularly spindle formation and centrosome assembly in mitosis, chromosome concentration and separation [ 5 , 27 ]. Furthermore, multiple studies have demonstrated that KIF4A is closely correlated with the occurrence and development of various malignancies, such as lung adenocarcinoma [ 34 ], hepatocellular carcinoma [ 15 ], colorectal cancer [ 14 ], prostate cancer [ 5 ].…”

Identification of the Signature Associated With m6A RNA Methylation Regulators and m6A-Related Genes and Construction of the Risk Score for Prognostication in Early-Stage Lung Adenocarcinoma

“…More and more evidence shows that KIF members are involved in the development and progression of human cancers (36)(37)(38). KIF4A is reported to be abnormally expressed and plays an important role in the progression of various solid cancers (28,39,40).…”

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

“…The expression of AR-V7 was found to be associated with the development of drug resistance (enzalutamide, abiraterone) and aggressive behavior in CRPC cells [ 84 ]. In nude mice harboring human CRPC cell xenografts, treatment with abiraterone significantly increased AR-V7 expression while AR-V7 overexpression promoted tumor growth and invasiveness [ 85 , 86 ]; in line with this observation, targeting this receptor variant was reported to suppress tumor growth and to confer sensitivity to antiandrogens (enzalutamide) [ 87 ]. In humans, the expression of AR-V7 was observed in tumor biopsies from CRPC patients and significantly correlated with tumor progression and short survival [ 88 , 89 , 90 , 91 , 92 ].…”