REG{gamma} controls Hippo signaling and reciprocal NF-{kappa}B-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 REG and NF-kappaB (NF-B) 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 REG deficient colon cancer cell lines, REG knockout mice and human CRC samples to identify the novel molecular mechanism by which REG functions as an oncoprotein in the development of colorectal cancer. Results: REG can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REG deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REG depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of YAP and NF-B pathways was observed in human colon cancer cells. REG 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 REG, YAP and p-p65. Conclusions: REG could be a master regulator during CRC development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and that REG could be a new marker for prognosis of CRC patients.

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