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

Developmental cell | 2019

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.

Pubmed ID: 30595538 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

None found

Antibodies used in this publication

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P01 CA203655
  • Agency: NCI NIH HHS, United States
    Id: R01 CA200651
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM094777
  • Agency: NCI NIH HHS, United States
    Id: R01 CA200573
  • Agency: NCI NIH HHS, United States
    Id: K99 CA212292
  • Agency: NCI NIH HHS, United States
    Id: R01 CA177910
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM089763
  • Agency: NCI NIH HHS, United States
    Id: R01 CA063113
  • Agency: NCI NIH HHS, United States
    Id: R01 CA229307

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HA-probe Antibody (Y-11) (antibody)

RRID:AB_631618

This polyclonal targets HA-probe

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Anti-Mouse IgG (whole molecule)-Peroxidase antibody produced in goat (antibody)

RRID:AB_258167

This polyclonal targets Mouse IgG (whole molecule)-Peroxidase antibody produced in goat

View all literature mentions

p27 (N-20) (antibody)

RRID:AB_632131

This polyclonal targets p27 (N-20)

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HA-influenza (antibody)

RRID:AB_257974

This monoclonal targets HA

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HA.11 Clone 16B12 Monoclonal Antibody, Purified (antibody)

RRID:AB_10064068

This monoclonal targets HA.11 Clone 16B12 Purified

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SPOP antibody (antibody)

RRID:AB_2756394

This polyclonal targets SPOP

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PE anti-human CD117 (c-kit) (antibody)

RRID:AB_314983

This monoclonal targets CD117

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Myc-Tag (9B11) Mouse mAb (antibody)

RRID:AB_331783

This monoclonal targets c-Myc

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Mouse IgG2A Alexa Fluor 488 Isotype Control (Clone 20102) (antibody)

RRID:AB_10718683

This unknown targets Mouse IgG2A Alexa Fluor 488 Isotype Control (Clone 20102)

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ANTI-FLAG(R) M2 Affinity Gel (antibody)

RRID:AB_10063035

This unknown targets ANTI-FLAG(R) M2 Affinity Gel

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cyclin A (H-432) (antibody)

RRID:AB_631329

This polyclonal targets CCNA2

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CUL3 Antibody (antibody)

RRID:AB_2086432

This polyclonal targets Cul3

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GST (91G1) Rabbit mAb (antibody)

RRID:AB_490796

This monoclonal targets GST (91G1) Rabbit mAb

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Anti-Nanog, N-terminus (antibody)

RRID:AB_2267042

This polyclonal targets Nanog

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cyclin E (HE12) (antibody)

RRID:AB_627357

This monoclonal targets cyclin E (HE12)

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SPOP antibody (antibody)

RRID:AB_2756394

This polyclonal targets SPOP

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Anti-Nanog, N-terminus (antibody)

RRID:AB_2267042

This polyclonal targets Nanog

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CUL3 Antibody (antibody)

RRID:AB_2086432

This polyclonal targets Cul3

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HA-probe Antibody (Y-11) (antibody)

RRID:AB_631618

This polyclonal targets HA-probe

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cyclin A (H-432) (antibody)

RRID:AB_631329

This polyclonal targets CCNA2

View all literature mentions

Myc-Tag (9B11) Mouse mAb (antibody)

RRID:AB_331783

This monoclonal targets c-Myc

View all literature mentions

p27 (N-20) (antibody)

RRID:AB_632131

This polyclonal targets p27 (N-20)

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cyclin E (HE12) (antibody)

RRID:AB_627357

This monoclonal targets cyclin E (HE12)

View all literature mentions

GST (91G1) Rabbit mAb (antibody)

RRID:AB_490796

This monoclonal targets GST (91G1) Rabbit mAb

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ANTI-FLAG(R) M2 Affinity Gel (antibody)

RRID:AB_10063035

This unknown targets ANTI-FLAG(R) M2 Affinity Gel

View all literature mentions

HA-influenza (antibody)

RRID:AB_257974

This monoclonal targets HA

View all literature mentions

HA.11 Clone 16B12 Monoclonal Antibody, Purified (antibody)

RRID:AB_10064068

This monoclonal targets HA.11 Clone 16B12 Purified

View all literature mentions

PE anti-human CD117 (c-kit) (antibody)

RRID:AB_314983

This monoclonal targets CD117

View all literature mentions

Anti-Mouse IgG (whole molecule)-Peroxidase antibody produced in goat (antibody)

RRID:AB_258167

This polyclonal targets Mouse IgG (whole molecule)-Peroxidase antibody produced in goat

View all literature mentions

Mouse IgG2A Alexa Fluor 488 Isotype Control (Clone 20102) (antibody)

RRID:AB_10718683

This unknown targets Mouse IgG2A Alexa Fluor 488 Isotype Control (Clone 20102)

View all literature mentions