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      Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer

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          Abstract

          Background

          Estrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). The G protein-coupled estrogen receptor (GPER) has been reported to mediate non-genomic effects of estrogen in hormone related cancers except CRC. Its expression and functions in CRC were investigated.

          Methods

          The expression of GPER and its associations with clinicopathological features were examined. The mechanisms were further investigated using cells, mouse xenograft models, and clinical human samples.

          Results

          GPER was significantly ( p < 0.01) down regulated in CRC tissues compared with their matched adjacent normal tissues in our two cohorts and three independent investigations from Oncomine database. Patients whose tumors expressing less ( n = 36) GPER showed significant ( p < 0.01) poorer survival rate as compared with those with greater levels of GPER ( n = 54). Promoter methylation and histone H3 deacetylation were involved in the down regulation of GPER in CRC cell lines and clinical tissues. Activation of GPER by its specific agonist G-1 inhibited proliferation, induced cell cycle arrest, mitochondrial-related apoptosis and endoplasmic reticulum (ER) stress of CRC cells. The upregulation of reactive oxygen species (ROS) induced sustained ERK1/2 activation participated in G-1 induced cell growth arrest. Further, G-1 can inhibit the phosphorylation, nuclear localization, and transcriptional activities of NF-κB via both canonical IKKα/ IκBα pathways and phosphorylation of GSK-3β. Xenograft model based on HCT-116 cells confirmed that G-1 can suppress the in vivo progression of CRC.

          Conclusions

          Epigenetic down regulation of GPER acts as a tumor suppressor in colorectal cancer and its specific activation might be a potential approach for CRC treatment.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12943-017-0654-3) contains supplementary material, which is available to authorized users.

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          Most cited references33

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          How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?

          Yohannes Mebratu, Yohannes Tesfaigzi (2009)
          Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase super family that can mediate cell proliferation and apoptosis. The Ras-Raf-MEK-ERK signaling cascade controlling cell proliferation has been well studied but the mechanisms involved in ERK1/2-mediated cell death are largely unknown. This review focuses on recent papers that define ERK1/2 translocation to the nucleus and the proteins involved in the cytosolic retention of activated ERK1/2. Cytosolic retention of ERK1/2 denies access to the transcription factor substrates that are responsible for the mitogenic response. In addition, cytosolic ERK1/2, besides inhibiting survival and proliferative signals in the nucleus, potentiates the catalytic activity of some proapoptotic proteins such as DAP kinase in the cytoplasm. Studies that further define the function of cytosolic ERK1/2 and its cytosolic substrates that enhance cell death will be essential to harness this pathway for developing effective treatments for cancer and chronic inflammatory diseases.
          Article 0 comments Cited 307 times – based on 0 reviews     Review now
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            40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971-2011: a population-based study.

            Manuela Quaresma, Michel Coleman, Bernard Rachet (2015)
            Assessment of progress in cancer control at the population level is increasingly important. Population-based survival trends provide a key insight into the overall effectiveness of the health system, alongside trends in incidence and mortality. For this purpose, we aimed to provide a unique measure of cancer survival.
            Article 0 comments Cited 191 times – based on 0 reviews     Review now
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              Virtual and biomolecular screening converge on a selective agonist for GPR30.

              Cristian Bologa, Chetana M Revankar, Susan M. Young … (2006)
              Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
              Article 0 comments Cited 190 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Hongsheng Wang: whongsh@mail.sysu.edu.cn , hongshengwang@foxmail.com
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 5 May 2017
                Publication date PMC-release: 5 May 2017
                Publication date Collection: 2017
                Volume: 16
                Electronic Location Identifier: 87
                Affiliations
                [1 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Microbial and Biochemical Pharmacy, , School of Pharmaceutical Sciences, Sun Yat-sen University, ; Guangzhou, 510006 China
                [2 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Sun Yat-sen University Cancer Center, , State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, ; Guangzhou, 510060 China
                [3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, , Central South University, ; Changsha, 410013 China
                [4 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, , Institute of Human Virology, Key Laboratory of Tropical Disease Control (Ministry of Education), Sun Yat-sen University, ; Guangzhou, 510655 China
                Article
                Publisher ID: 654
                DOI: 10.1186/s12943-017-0654-3
                PMC ID: 5418684
                PubMed ID: 28476123
                SO-VID: 45075e26-d962-473f-8bf8-1ef5b7c330d6
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 4 January 2017
                Date accepted : 24 April 2017
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 81673454
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gper,g-1,crc,nf-κb,ros
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: gper, g-1, crc, nf-κb, ros

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