The activity of signal transducer and activator of transcription 3 (STAT3) is delicately regulated to ensure proper physiological functions, such as cell proliferation, cell survival and cell differentiation. Aberrant activation of STAT3 results in serious diseases, including autoimmune disorders and cancer. However, the mechanisms on how STAT3 activity is regulated are not fully understood. And it remains unclear whether there are additional regulators of STAT3 activity.

In a joint study with Prof. XIA Huimin from Guangzhou Women and Children’s Medical Center, Prof. WANG Yanyi from Wuhan Institute of Virology of the Chinese Academy of Sciences, has identified a molecule, called FAM64A, as a positive regulator of STAT3 activity.

They performed a large-scale screen to identify candidate proteins that regulate STAT3 activity by reporter assays, and found that FAM64A could potentiate IL-6-induced STAT3 activation. Then they provided compelling evidence showing that FAM64A interacts with STAT3 in the nucleus and regulates binding of STAT3 to the promoters of its target genes.

Furthermore, to investigate the physiological function of FAM64A, they generated gene knockout mice. Through in vitro T cell differentiation and experimental autoimmune encephalomyelitis model, they found that FAM64A is a positive regulator of Th17 differentiation both in vitro and in vivo.

Moreover, using dextran sulfate sodium (DSS)-induced colitis model, they found that Fam64a-deficient mice developed less severe colitis compared with their wild-type littermates. Accordingly, there were also decreased Th17 cells in the colon of Fam64a-deficient mice. In addition, it was also observed that Fam64a deficiency suppressed azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) in mice.

"This study reveals a previously unreported function of FAM64A in the regulation of STAT3 activity, inflammation and tumorigenesis. It provides a potentially new therapeutic target for inflammatory diseases and cancer." said Prof. WANG Yanyi, the principal investigator and the corresponding author of the paper.

"The author's findings are novel and original, and discover a novel and interesting mechanism regulating the activity of an important protein STAT3 that plays broad roles in immunity and cancer," commented by a reviewer of the paper.

Their study was published online recently in PNAS entitled “FAM64A positively regulates STAT3 activity to promote Th17 differentiation and colitis-associated carcinogenesis”.

This work was supported by the National Science Fund for Distinguished Young Scholars, the Strategic Priority Research Program and Key Research Programs of Frontier Science funded by Chinese Academy of Sciences and the National Natural Science Foundation of China. Researchers from Wuhan University also participated in this study.

A proposed model for FAM64A-mediated regulation of STAT3 activity, Th17 differentiation and CAC development. Image by WANG Yanyi