Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6

Abstract

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation and immune signaling pathways and maintained gene expression patterns normal decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer.

Expression of the NEK family in normal and cancer tissue: an immunohistochemical study

“…Different groups have studied each member of this protein family separately and have observed that the expression of many of them is altered in cancers tissues. The expression of NEK2, NEK6, and NEK11 were related to colorectal cancer [30,[38][39][40], NEK2, NEK3, NEK5, NEK6, and NEK8 to breast cancer [11,[41][42][43][44][45], and NEK2 and NEK6 to prostate cancer [16,46].…”

Checking NEKs: Overcoming a Bottleneck in Human Diseases

“…Conversely, it was also reported that the reduction of NEK6 expression reestablished castration sensitivity. The study suggested that NEK6 may be related to cell survival pathways since no significant changes in proliferation or cell cycle progression were observed in NEK6 overexpressing prostate cancer cells [140].…”

“…In recent years, altered expression and activity of NEK6 were associated with several types of cancer, such as liver [139], prostate [140], gastric [141][142][143], colorectal [144,145], breast [146], serous epithelial ovarian [147], thyroid [148], and retinoblastoma cancers [149]. In addition, inflammation-based diseases, such as ulcerative colitis, have also been linked to NEK6 [28].…”

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

“…We implanted cell xenografts subcutaneously (Choudhury et al, 2017) in the two flanks of immuno-deficient male BALB/C (BALBNU, Taconic) mice under Dana-Farber Cancer Institute IACUC protocol 03–013. Approximately 2 million cells were implanted with matrigel at a 1:1 ratio.…”