FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitisassociated carcinogenesis

Zhi Sheng Xu, Hong Xia Zhang, Wei Wei Li, Yong Ran, Tian Tian Liu, Mei Guang Xiong, Qing Lan Li, Su Yun Wang, Min Wu, Hong Bing Shu, Huimin Xia, Yan Yi Wang

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

STAT3 is a transcription factor that plays central roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. The mechanisms related to how STAT3 activity is regulated remain enigmatic. Here we show that overexpression of FAM64A potentiates IL-6-induced activation of STAT3 and expression of downstream target genes, whereas deficiency of FAM64A has the opposite effects. FAM64A interactswith STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes. Deficiency of Fam64a significantly impairs differentiation of Th17 but not Th1 or induced regulatory T cells (iTreg). In addition, Fam64a deficiency attenuates experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, which is correlated with decreased differentiation of Th17 cells and production of proinflammatory cytokines. Furthermore, Fam64a deficiency suppresses azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice. These findings suggest that FAM64A regulates Th17 differentiation and colitis and inflammation-associated cancer by modulating transcriptional activity of STAT3.

Original languageEnglish
Pages (from-to)10447-10452
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number21
DOIs
StatePublished - 2019

Keywords

  • CAC
  • colitis
  • FAM64A
  • STAT3
  • Th17

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