NEK1-Mediated Phosphorylation of YAP1 is key to Prostate Cancer Progression

Abstract

Understanding how Androgen-dependent PCa cells progress to independence and modify accordingly their transcriptional repertoire is the key to preventing mCRPC progression. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation: AR->TLK1B>NEK1>pYAP1-Y407 leading to CRPC adaptation. Phosphorylation of YAP-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduced TEAD- and P73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and if castrated fail to progress to overt prostate carcinomas, even while displaying reduced E-CAD expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen independent growth and a mesenchymal morphology. Immunohistochemical examination of Prostate Cancer biopsies revealed that pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus, leading to degradation of YAP1 can suppress the transcriptional reprogramming of LNCaP cells to Androgen-Independent growth and EMT progression even when YAP1-WT is overexpressed.