Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition

Jiantong Jiao, Rui Zhang, Zheng Li, Ying Yin, Xiangming Fang, Xiaopeng Ding, Ying Cai, Shudong Yang, Huijun Mu, Da Zong, Yuexin Chen, Yansong Zhang, Jian Zou (), Junfei Shao () and Zhaohui Huang ()
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Jiantong Jiao: Wuxi People’s Hospital of Nanjing Medical University
Rui Zhang: Wuxi People’s Hospital of Nanjing Medical University
Zheng Li: Wuxi People’s Hospital of Nanjing Medical University
Ying Yin: Wuxi People’s Hospital of Nanjing Medical University
Xiangming Fang: Wuxi People’s Hospital of Nanjing Medical University
Xiaopeng Ding: Wuxi People’s Hospital of Nanjing Medical University
Ying Cai: Wuxi People’s Hospital of Nanjing Medical University
Shudong Yang: Wuxi People’s Hospital of Nanjing Medical University
Huijun Mu: Wuxi People’s Hospital of Nanjing Medical University
Da Zong: Wuxi People’s Hospital of Nanjing Medical University
Yuexin Chen: Wuxi People’s Hospital of Nanjing Medical University
Yansong Zhang: Nanjing Brain Hospital of Nanjing Medical University
Jian Zou: Wuxi People’s Hospital of Nanjing Medical University
Junfei Shao: Wuxi People’s Hospital of Nanjing Medical University
Zhaohui Huang: Affiliated Hospital of Jiangnan University

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

Date: 2018
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DOI: 10.1038/s41467-018-04936-9

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