Abstract
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 REGγ and NF-kappaB (NF-κB) 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 REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer 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 the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ 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 REGγ, YAP, and p-p65.Conclusions: REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015-25. ©2018 AACR.
Highlights
Colorectal cancer is one of the most commonly diagnosed cancers in both men and women
REGg can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells
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
Summary
Given that patients with ulcerative colitis have an increased risk of developing colorectal cancer, our discovery of REGg as an activator of bowel inflammation prompted us to investigate its link with human colon cancer. An interesting observation was that the differences of Lats and YAP levels in nontumor colon tissues between REGgþ/þ and REGgÀ/À mice were boosted in tumor samples (Fig. 3D) These data raise a possibility that Hippo–YAP activity was further enhanced by cross-talk with other signals regulated by augmented REGg during tumorigenesis. Activation of NF-kB by TNFa or IL6 significantly induced expression of AREG, CTGF, and Cyr, but attenuated transcription of Trail and DDIT4 in HCT116 or HT29 cell lines (Fig. 4C and D; Supplementary Fig. S6C and S6D), establishing a positive regulation by the NF-kB signal on the YAP pathway. REGgþ/þ and REGgÀ/À mice were treated with 2% DSS for 5 days, and the mRNA levels of AREG and CTGF in the mouse colon tissues were quantified by real-time RT-PCR analysis (ANOVA, n 1⁄4 3; ÃÃ, P < 0.01; ÃÃÃ, P < 0.001).
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