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; Zhaohui Huang

doi:10.1038/s41467-018-04936-9

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

Nat Commun. 2018 Jun 27;9(1):2504. doi: 10.1038/s41467-018-04936-9.

Authors

Jiantong Jiao^{1

2

3}, Rui Zhang^{1

2}, Zheng Li^{1

2

3}, Ying Yin^{1

3}, Xiangming Fang⁴, Xiaopeng Ding^{1

2}, Ying Cai⁵, Shudong Yang⁵, Huijun Mu^{1

3}, Da Zong², Yuexin Chen^{1

3}, Yansong Zhang⁶, Jian Zou^{7

8}, Junfei Shao^{9

10}, Zhaohui Huang¹¹

Affiliations

¹ Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
² Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
³ Wuxi Institute of Translational Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
⁴ Department of Radiology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
⁵ Department of Pathology, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
⁶ Department of Neurosurgery, Nanjing Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
⁷ Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China. [email protected].
⁸ Wuxi Institute of Translational Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China. [email protected].
⁹ Department of Neurosurgery, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China. [email protected].
¹⁰ Wuxi Institute of Translational Medicine, Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, 214023, China. [email protected].
¹¹ Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Brain / pathology
Brain Neoplasms / genetics
Brain Neoplasms / mortality
Brain Neoplasms / pathology*
Carcinogenesis / pathology
Cell Line, Tumor
Cell Nucleus / metabolism
Cell Proliferation / genetics
Cohort Studies
Down-Regulation
Female
Gene Expression Regulation, Neoplastic
Glioma / genetics
Glioma / mortality
Glioma / pathology*
HEK293 Cells
Humans
Infant
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Molecular Chaperones / metabolism*
Protein Domains
Protein Inhibitors of Activated STAT / metabolism*
Proteolysis
STAT3 Transcription Factor / metabolism*
Signal Transduction / genetics
Smad6 Protein / metabolism*
Survival Rate
Ubiquitin-Protein Ligases
Ubiquitination / genetics
Up-Regulation
Xenograft Model Antitumor Assays
Young Adult

Substances

Molecular Chaperones
PIAS3 protein, human
Protein Inhibitors of Activated STAT
SMAD6 protein, human
STAT3 Transcription Factor
STAT3 protein, human
Smad6 Protein
SMURF1 protein, human
Ubiquitin-Protein Ligases