Proceedings of the National Academy of Sciences | 2019
FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis
Abstract
Significance The transcription factor STAT3 plays pivotal roles in various physiological processes, including differentiation of Th cells. Its deregulation results in serious diseases, including inflammatory diseases and cancer. Understanding how STAT3 activity is regulated is important for deciphering the pathogenesis of such diseases. In this study, we identified a protein called FAM64A, which promotes STAT3 activity through modulating the DNA-binding activity of STAT3. Consequently, FAM64A also promotes Th17 differentiation and development of colitis and colitis-associated cancer. This study reveals a previously unreported function of FAM64A in the regulation of inflammation and tumorigenesis and provides a potential therapeutic target for inflammatory diseases and cancer. 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 interacts with 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.