2. Academic Validation
  3. SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression

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

  • Dev Cell. 2019 Feb 11;48(3):329-344.e5. doi: 10.1016/j.devcel.2018.11.035.
Jinfang Zhang 1,  Ming Chen 2,  Yasheng Zhu 3,  Xiangpeng Dai 1,  Fabin Dang 1,  Junming Ren 1,  Shancheng Ren 3,  Yulia V Shulga 4,  Francisco Beca 5,  Wenjian Gan 1,  Fei Wu 6,  Yu-Min Lin 7,  Xiaobo Zhou 8,  James A DeCaprio 9,  Andrew H Beck 1,  Kun Ping Lu 7,  Jiaoti Huang 10,  Cheryl Zhao 11,  Yinghao Sun 3,  Xu Gao 12,  Pier Paolo Pandolfi 13,  Wenyi Wei 14
Affiliations

Affiliations

  • 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 3 Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • 4 Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 5 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
  • 6 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 7 Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 8 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 10 Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 11 Stemmera Inc, 3475 Edison Way Suite J2, Menlo Park, CA 94025, USA.
  • 12 Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: gaoxu.changhai@foxmail.com.
  • 13 Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: ppandolf@bidmc.harvard.edu.
  • 14 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.
PMID: 30595538 DOI: 10.1016/j.devcel.2018.11.035
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.

Keywords

Nanog; Pin1; PrCa; SPOP; phosphorylation; prostate cancer; stem cell; ubiquitination.

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