REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer

Purpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REG gamma and NF-kappaB (NF-kappa B) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown. Experimental Design: Here, we used REG gamma-deficient colon cancer cell lines, REG gamma knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REG gamma functions as an oncoprotein in the development of colorectal cancer. Results: REG gamma can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REG gamma deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REG gamma depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-kappa B pathways was observed in human colon cancer cells. REG gamma overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REG gamma, YAP, and p-p65. Conclusions: REG gamma could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REG gamma might be a new marker for prognosis of colorectal cancer patients. (C) 2018 AACR.