REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Lei Li; Yongyan Dang; Jishen Zhang; Wangjun Yan; Wanli Zhai; Hui Chen; Ke Li; Lu Tong; Xiao Gao; Ali Amjad; Lei Ji; Tiantian Jing; Ziwei Jiang; Kaixuan Shi; Liangfang Yao; Dianwen Song; Tielong Liu; Xinghai Yang; Cheng Yang; Xiaopan Cai; Wei Xu; Quan Huang; Jin He; Jian Liu; Tenghui Chen; Robb E Moses; Junjiang Fu; Jianru Xiao; Xiaotao Li

doi:10.1038/ncomms7875

REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway

Nat Commun. 2015 Apr 24:6:6875. doi: 10.1038/ncomms7875.

Authors

Lei Li^{1

2}, Yongyan Dang², Jishen Zhang¹, Wangjun Yan¹, Wanli Zhai², Hui Chen², Ke Li², Lu Tong², Xiao Gao², Ali Amjad², Lei Ji², Tiantian Jing², Ziwei Jiang², Kaixuan Shi², Liangfang Yao², Dianwen Song¹, Tielong Liu¹, Xinghai Yang¹, Cheng Yang¹, Xiaopan Cai¹, Wei Xu¹, Quan Huang¹, Jin He¹, Jian Liu³, Tenghui Chen⁴, Robb E Moses³, Junjiang Fu⁵, Jianru Xiao¹, Xiaotao Li³

Affiliations

¹ Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
² Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
³ Department of Molecular Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
⁴ Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.
⁵ Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.

PMID: 25908095
DOI: 10.1038/ncomms7875

Abstract

Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantigens / genetics*
Autoantigens / metabolism
Carcinogenesis / genetics*
Carcinogens / pharmacology
Cell Line
Cell Proliferation / genetics
Cyclin D1 / metabolism
Gene Knockdown Techniques
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Keratinocytes / cytology
Keratinocytes / drug effects
Keratinocytes / metabolism*
Mice
Mice, Knockout
Proteasome Endopeptidase Complex / genetics*
Proteasome Endopeptidase Complex / metabolism
Proto-Oncogene Proteins c-myc / metabolism
Skin Neoplasms / chemically induced
Skin Neoplasms / genetics*
Skin Neoplasms / metabolism
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factor AP-1 / metabolism
Wnt Signaling Pathway*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors

Substances

Autoantigens
Carcinogens
Ccnd1 protein, mouse
Ki antigen
Myc protein, mouse
Proto-Oncogene Proteins c-myc
Transcription Factor AP-1
Cyclin D1
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
p38 Mitogen-Activated Protein Kinases
Glycogen Synthase Kinase 3
Proteasome Endopeptidase Complex
Tetradecanoylphorbol Acetate