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

Qingwei Wang, Xiao Gao, Tong Yu, Lei Yuan, Jie Dai, Weicang Wang, Geng Chen, Chan Jiao, Wang Zhou, Quan Huang, Long Cui, Pei Zhang, Robb Moses, Jianhua Yang, Fengyuan Chen, Junjiang Fu, Jianru Xiao, Lei Li, Yongyan Dang, Xiaotao Li

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2015-2025
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2018
Externally publishedYes

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Colonic Neoplasms
Colorectal Neoplasms
Proteins
NF-kappa B
Growth
Inflammation
Oncogene Proteins
Proteasome Endopeptidase Complex
Colitis
Knockout Mice
Neoplasms
Colon
Research Design
Survival Rate
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

REGg controls hippo signaling and reciprocal NF-kB–YAP regulation to promote colon cancer. / Wang, Qingwei; Gao, Xiao; Yu, Tong; Yuan, Lei; Dai, Jie; Wang, Weicang; Chen, Geng; Jiao, Chan; Zhou, Wang; Huang, Quan; Cui, Long; Zhang, Pei; Moses, Robb; Yang, Jianhua; Chen, Fengyuan; Fu, Junjiang; Xiao, Jianru; Li, Lei; Dang, Yongyan; Li, Xiaotao.

In: Clinical Cancer Research, Vol. 24, No. 8, 15.04.2018, p. 2015-2025.

Research output: Contribution to journalArticle

Wang, Q, Gao, X, Yu, T, Yuan, L, Dai, J, Wang, W, Chen, G, Jiao, C, Zhou, W, Huang, Q, Cui, L, Zhang, P, Moses, R, Yang, J, Chen, F, Fu, J, Xiao, J, Li, L, Dang, Y & Li, X 2018, 'REGg controls hippo signaling and reciprocal NF-kB–YAP regulation to promote colon cancer', Clinical Cancer Research, vol. 24, no. 8, pp. 2015-2025. https://doi.org/10.1158/1078-0432.CCR-17-2986
Wang, Qingwei ; Gao, Xiao ; Yu, Tong ; Yuan, Lei ; Dai, Jie ; Wang, Weicang ; Chen, Geng ; Jiao, Chan ; Zhou, Wang ; Huang, Quan ; Cui, Long ; Zhang, Pei ; Moses, Robb ; Yang, Jianhua ; Chen, Fengyuan ; Fu, Junjiang ; Xiao, Jianru ; Li, Lei ; Dang, Yongyan ; Li, Xiaotao. / REGg controls hippo signaling and reciprocal NF-kB–YAP regulation to promote colon cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 8. pp. 2015-2025.
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abstract = "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.",
author = "Qingwei Wang and Xiao Gao and Tong Yu and Lei Yuan and Jie Dai and Weicang Wang and Geng Chen and Chan Jiao and Wang Zhou and Quan Huang and Long Cui and Pei Zhang and Robb Moses and Jianhua Yang and Fengyuan Chen and Junjiang Fu and Jianru Xiao and Lei Li and Yongyan Dang and Xiaotao Li",
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T1 - REGg controls hippo signaling and reciprocal NF-kB–YAP regulation to promote colon cancer

AU - Wang, Qingwei

AU - Gao, Xiao

AU - Yu, Tong

AU - Yuan, Lei

AU - Dai, Jie

AU - Wang, Weicang

AU - Chen, Geng

AU - Jiao, Chan

AU - Zhou, Wang

AU - Huang, Quan

AU - Cui, Long

AU - Zhang, Pei

AU - Moses, Robb

AU - Yang, Jianhua

AU - Chen, Fengyuan

AU - Fu, Junjiang

AU - Xiao, Jianru

AU - Li, Lei

AU - Dang, Yongyan

AU - Li, Xiaotao

PY - 2018/4/15

Y1 - 2018/4/15

N2 - 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.

AB - 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.

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EP - 2025

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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