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

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.

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Citation

Published Version (Please cite this version)

10.1016/j.devcel.2018.11.035

Publication Info

Zhang, Jinfang, Ming Chen, Yasheng Zhu, Xiangpeng Dai, Fabin Dang, Junming Ren, Shancheng Ren, Yulia V Shulga, et al. (2019). SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression. Developmental cell, 48(3). pp. 329–344.e5. 10.1016/j.devcel.2018.11.035 Retrieved from https://hdl.handle.net/10161/20384.

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Scholars@Duke

Chen

Ming Chen

Associate Professor in Pathology

Our laboratory is interested in understanding the molecular and genetic events underlying cancer progression and metastasis. The focus of our work is a series of genetically engineered mouse models that faithfully recapitulate human disease. Using a combination of mouse genetics, omics technologies, cross-species analyses and in vitro approaches, we aim to identify cancer cell–intrinsic and –extrinsic mechanisms driving metastatic cancer progression, with a long–term goal of developing new therapeutic strategies for preventing and treating metastatic disease. 

Huang

Jiaoti Huang

The Johnston-West Endowed Department Chair of Pathology

I am a physician-scientist with clinical expertise in the pathologic diagnosis of genitourinary tumors including tumors of the prostate, bladder, kidney and testis. Another area of interest is gynecologic tumors. In my research laboratory we study prostate cancer, focusing on molecular mechanisms of carcinogenesis and tumor progression, as well as biomarkers, imaging and novel therapeutic strategies. In addition to patient care and research, I am also passionate about education. I have trained numerous residents, fellows, graduate students and postdocs.


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