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

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