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

Qiao Liu,Jun Du,Guanmin Jiang,Huanliang Liu,Zhuojia Chen,Hongbin Huang,Xiangling Yang,Yan Zhou,Hongsheng Wang

doi:10.1186/s12943-017-0654-3

Abstract

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

Highlights

Estrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC)
Our present study and published data revealed that G protein-coupled estrogen receptor (GPER) is significantly down regulated in the CRC tissues as compared with the adjacent normal tissues and higher expression of GPER is correlated with favorable prognosis of CRC patients
Our results indicate that GPER functions as a tumor suppressor in CRC via activation of reactive oxygen species (ROS)/ERK1/2 and suppression of NF-κB

Summary

Introduction

Estrogenic signals are suggested to have protection roles in the development of colorectal cancer (CRC). Liu et al Molecular Cancer (2017) 16:87 cancer occurrence [6, 7] These data suggested that estrogenic signals might be involved and have protection roles in the development of this disease. From the phenotype of ER β−/− mice, there is more colitis-associated neoplasia [11] and ERβ in the colon appears to decrease proliferation and increase apoptosis [12] All these data suggested that ERβ is important for the tumor suppressive effect, while ERα is not widely expressed and its role in colon cancer has not been found so far [10]

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Conclusion