REG? Controls Hippo Signaling and Reciprocal NF-?B-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? and NF-kappaB (NF-?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?-deficient colon cancer cell lines, REG? knockout mice, and human colorectal cancer 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 the YAP and NF-?B pathways was observed in human colon cancer cells. REG? 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?, YAP, and p-p65.Conclusions: REG? could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REG? might be a new marker for prognosis of colorectal cancer patients. Clin Cancer Res; 24(8); 2015-25. ©2018 AACR.
Mesh Terms:
Animals, Autoantigens, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Colonic Neoplasms, Disease Models, Animal, Heterografts, Humans, Mice, NF-kappa B, Prognosis, Proteasome Endopeptidase Complex, Protein Binding, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction, Survival Analysis, Transcription Factors
Animals, Autoantigens, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Colonic Neoplasms, Disease Models, Animal, Heterografts, Humans, Mice, NF-kappa B, Prognosis, Proteasome Endopeptidase Complex, Protein Binding, Protein-Serine-Threonine Kinases, Proteolysis, Signal Transduction, Survival Analysis, Transcription Factors
Clin. Cancer Res.
Date: Dec. 15, 2017
PubMed ID: 29437787
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