Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer

Abstract

Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo Tumor suppressor pathway which regulates Yes 1 Associated protein (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulate YAP1/TAZ activation and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyper-activation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. A high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth and matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo and biochemical analysis suggest a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemo-protective effects. Our results contend that STK3 has a non-canonical role in PC progression and inhibition of STK3 may have therapeutic potential for PC that merits further investigation. SignificanceOur findings illuminate a new actionable target for PC therapy that would traditionally be overlooked due to its canonical role as a tumor suppressor in other cancer types.