Myc-Associated Zinc Finger Protein Regulates the Proinflammatory Response in Colitis and Colon Cancer via STAT3 Signaling

ABSTRACT

Myc-associated zinc finger (MAZ) is a transcription factor highly upregulated in chronic inflammatory disease and several human cancers. In the present study, we found that MAZ protein is highly expressed in human ulcerative colitis and colon cancer. However, the precise role for MAZ in the progression of colitis and colon cancer is not well defined. To determine the function of MAZ, a novel mouse model of intestinal epithelial cell-specific MAZ overexpression was generated. Expression of MAZ in intestinal epithelial cells was sufficient to enhance inflammatory injury in two complementary models of colitis. Moreover, MAZ expression increased tumorigenesis in an in vivo model of inflammation-induced colon cancer and was important for growth of human colon cancer cell lines in vitro and in vivo. Mechanistically, MAZ is critical in the regulation of oncogenic STAT3 signaling. MAZ-expressing mice have enhanced STAT3 activation in the acute response to colitis. Moreover, MAZ was essential for cytokine- and bacterium-induced STAT3 signaling in colon cancer cells. Furthermore, we show that STAT3 is essential for MAZ-induced colon tumorigenesis using a chemical inhibitor. These data indicate an important functional role for MAZ in the inflammatory progression of colon cancer through regulation of STAT3 signaling and suggest that MAZ is a potential therapeutic target to dampen STAT3 signaling in colon cancer.

KEYWORDS:

• inflammation
• STAT3
• MAZ
• colitis
• colon cancer

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00386-18.

ACKNOWLEDGMENTS

This study was supported by NIH grants CA148828 and DK095201 to Y.M.S., grant ES028802 to J.A.C., the University of Michigan Gastrointestinal Peptide Center (Y.M.S.), and a pilot grant from the University of Michigan GI Spore (CA130810 to Y.M.S.). D.T. was supported by NIH grant F30CA213664.