REGg controls hippo signaling and reciprocal NF-kB–YAP regulation to promote colon cancer

Purpose: Colorectal cancer is one of the most commonly diag-nosedcancerscloselyassociatedwithinflammationandhyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGg and NF-kappaB (NF-kB) 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 REGg-deficient colon cancer cell lines, REGg knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGg functions as an oncoprotein in the development of colorectal cancer. Results: REGg can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGg deficiency significantly atten-uatedcoloncancergrowth,associatedwithdecreasedYAPactivity. Suppression of tumor growth due to REGg depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-kB pathways was observed in human colon cancer cells. REGg 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 REGg, YAP, and p-p65. Conclusions: REGg could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGg might be a new marker for prognosis of colorectal cancer patients.