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 () and Xiaotao Li
Additional contact information
Lei Li: Changzheng Hospital, The Second Military Medical University
Yongyan Dang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Jishen Zhang: Changzheng Hospital, The Second Military Medical University
Wangjun Yan: Changzheng Hospital, The Second Military Medical University
Wanli Zhai: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Hui Chen: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Ke Li: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Lu Tong: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Xiao Gao: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Ali Amjad: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Lei Ji: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Tiantian Jing: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Ziwei Jiang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Kaixuan Shi: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Liangfang Yao: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University
Dianwen Song: Changzheng Hospital, The Second Military Medical University
Tielong Liu: Changzheng Hospital, The Second Military Medical University
Xinghai Yang: Changzheng Hospital, The Second Military Medical University
Cheng Yang: Changzheng Hospital, The Second Military Medical University
Xiaopan Cai: Changzheng Hospital, The Second Military Medical University
Wei Xu: Changzheng Hospital, The Second Military Medical University
Quan Huang: Changzheng Hospital, The Second Military Medical University
Jin He: Changzheng Hospital, The Second Military Medical University
Jian Liu: Dan L. Duncan Cancer Center, Baylor College of Medicine
Tenghui Chen: MD Anderson Cancer Center, The University of Texas
Robb E. Moses: Dan L. Duncan Cancer Center, Baylor College of Medicine
Junjiang Fu: Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College
Jianru Xiao: Changzheng Hospital, The Second Military Medical University
Xiaotao Li: Dan L. Duncan Cancer Center, Baylor College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7875

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