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

Xinbo Wang; Jiali Jin; Fangning Wan; Linlin Zhao; Hongshang Chu; Cong Chen; Guanghong Liao; Jian Liu; Yue Yu; Hongqi Teng; Lan Fang; Cong Jiang; Weijuan Pan; Xin Xie; Jia Li; Xiaolin Lu; Xuejun Jiang; Xin Ge; Dingwei Ye; Ping Wang

doi:10.1016/j.devcel.2018.11.033

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

Dev Cell. 2019 Feb 11;48(3):345-360.e7. doi: 10.1016/j.devcel.2018.11.033. Epub 2018 Dec 27.

Authors

Xinbo Wang¹, Jiali Jin², Fangning Wan³, Linlin Zhao², Hongshang Chu⁴, Cong Chen⁴, Guanghong Liao⁴, Jian Liu⁵, Yue Yu⁴, Hongqi Teng⁶, Lan Fang⁶, Cong Jiang⁴, Weijuan Pan⁴, Xin Xie⁵, Jia Li⁵, Xiaolin Lu³, Xuejun Jiang⁷, Xin Ge⁸, Dingwei Ye⁹, Ping Wang¹⁰

Affiliations

¹ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Shanghai Putuo People's Hospital, School of Medicine, Tongji University, Shanghai 200060, China; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
² Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
³ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁴ Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
⁵ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁶ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China.
⁷ Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁸ Department of Clinical Medicine, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China. Electronic address: xin.ge@tongji.edu.cn.
⁹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: dwyeli@163.com.
¹⁰ Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China. Electronic address: wangp@tongji.edu.cn.

Abstract

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.

Keywords: AMPK-BRAF axis; NANOG; SPOP; prostate cancer stem cell; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Animals
Cell Line, Tumor
Cullin Proteins / metabolism
Genes, Tumor Suppressor
Humans
Male
Mice, Nude
Mutation / genetics
Nanog Homeobox Protein / metabolism*
Nuclear Proteins / metabolism*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Repressor Proteins / metabolism*
Transcription Factors / metabolism
Ubiquitination / physiology

Substances

Cullin Proteins
NANOG protein, human
Nanog Homeobox Protein
Nuclear Proteins
Repressor Proteins
SPOP protein, human
Transcription Factors
AMP-Activated Protein Kinases

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States