FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis

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 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.

FAM64A: A Novel Oncogenic Target of Lung Adenocarcinoma Regulated by Both Strands of miR-99a (miR-99a-5p and miR-99a-3p)

“…In breast cancer, overexpression of FAM64A enhanced the transactivation of NF-κB by disrupting the NF-κB/IκBα negative feedback loop [ 47 ]. Another study demonstrated that FAM64A regulates STAT3 activation and is involved in Th17 differentiation, colitis and colorectal cancer development [ 48 ]. These findings indicate that FAM64A behaves as a transcriptional regulator contributing to cell cycle progression.…”

FAM64A Promotes Osteosarcoma Cell Growth and Metastasis and Is Mediated by miR-493

“…e dysregulation of intracellular signaling pathways such as Notch1, Akt, Wnt pathway, and JAK2/STAT3 was reported to be participated in the development of OS [3][4][5][6]. Xu et al found that FAM64A served as a positive regulator of STAT3, which is linked to various cancer types [7]. Here, we tried to find a new mechanism that interacts with FAM64A in OS.…”

The Role of Adaptor Protein CARD9 in Colitis-Associated Cancer

“…The increased IL-6 expression could prompt STAT3 activation and greatly drive CAC tumorigenesis in mice, whereas IL-6 deletion suppressed the pro-carcinogenic effect 25, 26. IL-17A that was produced by Th17 cells directly promoted the progression of early non-neoplastic inflammatory epithelium into cancer, and the elevated expression of such cytokine, together with IL-23R, induced the development of CAC in colitis mice 27, 28, 29. On the other hand, cytotoxic T lymphocytes (CTLs) acted as tumor immunosurveillance, mounting vigorous immune responses against CAC tumor cells 30 …”