SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression.

dc.contributor.author

Zhang, Jinfang

dc.contributor.author

Chen, Ming

dc.contributor.author

Zhu, Yasheng

dc.contributor.author

Dai, Xiangpeng

dc.contributor.author

Dang, Fabin

dc.contributor.author

Ren, Junming

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Ren, Shancheng

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Shulga, Yulia V

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Beca, Francisco

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Gan, Wenjian

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Wu, Fei

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Lin, Yu-Min

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Zhou, Xiaobo

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DeCaprio, James A

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Beck, Andrew H

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Lu, Kun Ping

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Huang, Jiaoti

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Zhao, Cheryl

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Sun, Yinghao

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Gao, Xu

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Pandolfi, Pier Paolo

dc.contributor.author

Wei, Wenyi

dc.date.accessioned

2020-04-06T05:49:25Z

dc.date.available

2020-04-06T05:49:25Z

dc.date.issued

2019-02

dc.date.updated

2020-04-06T05:49:23Z

dc.description.abstract

Frequent SPOP mutation defines the molecular feature underlying one of seven sub-types of human prostate cancer (PrCa). However, it remains largely elusive how SPOP functions as a tumor suppressor in PrCa. Here, we report that SPOP suppresses stem cell traits of both embryonic stem cells and PrCa cells through promoting Nanog poly-ubiquitination and subsequent degradation. Mechanistically, Nanog, but not other pluripotency-determining factors including Oct4, Sox2, and Klf4, specifically interacts with SPOP via a conservative degron motif. Importantly, cancer-derived mutations in SPOP or at the Nanog-degron (S68Y) disrupt SPOP-mediated destruction of Nanog, leading to elevated cancer stem cell traits and PrCa progression. Notably, we identify the Pin1 oncoprotein as an upstream Nanog regulator that impairs its recognition by SPOP and thereby stabilizes Nanog. Thus, Pin1 inhibitors promote SPOP-mediated destruction of Nanog, which provides the molecular insight and rationale to use Pin1 inhibitor(s) for targeted therapies of PrCa patients with wild-type SPOP.

dc.identifier

S1534-5807(18)31018-9

dc.identifier.issn

1534-5807

dc.identifier.issn

1878-1551

dc.identifier.uri

https://hdl.handle.net/10161/20384

dc.language

eng

dc.publisher

Elsevier BV

dc.relation.ispartof

Developmental cell

dc.relation.isversionof

10.1016/j.devcel.2018.11.035

dc.subject

Stem Cells

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Humans

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Prostatic Neoplasms

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Disease Progression

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Cullin Proteins

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Nuclear Proteins

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Repressor Proteins

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Cell Proliferation

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Mutation

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Male

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Protein Interaction Domains and Motifs

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Ubiquitination

dc.title

SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression.

dc.type

Journal article

duke.contributor.orcid

Chen, Ming|0000-0002-3470-1062

duke.contributor.orcid

Huang, Jiaoti|0000-0003-1195-1998

pubs.begin-page

329

pubs.end-page

344.e5

pubs.issue

3

pubs.organisational-group

School of Medicine

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Pathology

pubs.organisational-group

Duke

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Pharmacology & Cancer Biology

pubs.organisational-group

Basic Science Departments

pubs.publication-status

Published

pubs.volume

48

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