AMPK Promotes SPOP-Mediated NANOG Degradation to Regulate Prostate Cancer Cell Stemness

NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa. [Display omitted] •SPOP targets NANOG for degradation•Cancer-associated SPOP mutants lost the ability to degrade NANOG•NANOG stability is regulated by AMPK-BRAF-mediated phosphorylation•SPOP represses prostate cancer stemness via targeting NANOG Wang et al. uncover a regulation mechanism by which NANOG stability, which is involved in the regulation of the stem-like characteristics of prostate cancer cells, is dictated by SPOP-mediated degradation and is controlled by AMPK-BRAF-mediated phosphorylation of NANOG at Ser68.