KBTBD11 loss promotes AKT hyperactivation and therapeutic vulnerability in prostate cancer.

Abstract

PI3K-AKT signaling axis is often aberrantly activated in human cancers including prostate cancer, but the underlying mechanism of deregulation and tactics for effective targeting of this cancer relevant pathway remain poorly understood. Here, we demonstrate that KBTBD11 E3 ubiquitin ligase gene is frequently deleted in human prostate cancers and that KBTBD11 loss augments AKT phosphorylation in prostate cancer cells in culture and in patient samples. We show that KBTBD11 promotes lysine-27-chain polyubiquitination at lysine 8 and 14 on AKT and antagonizes ubiquitin K63 linkage-mediated polyubiquitination and phosphorylation of AKT. KBTBD11 deficiency drove prostate cancer cell growth in vitro and in vivo, but constituted as a therapeutic vulnerability to the selective AKT inhibitor in prostate cancer. Our study identifies lysine-27-chain polyubiquitination as an inhibitory mechanism of AKT activation and nominates KBTBD11 as an intrinsic upstream inhibitor of AKT. Our findings suggest that KBTBD11 deletion could be a biomarker to guide the use of the AKT inhibitors for the effective treatment of cancers such as prostate cancer.