MiR-502 medaited histone methyltransferase SET8 expression is associated with outcome of esophageal squamous cell carcinoma.

Cuiju Wang,Jianhua Wu,Zhanjun Guo,Yue Zhao

doi:10.1038/srep32921

Abstract

The histone methyltransferase SET8, whose expression is regulated by miR-502 though the binding site in the 3′ UTR of SET8, implicated in cancer development. Single nucleotide polymorphism (SNP) of rs16917496 located in the miR-502 and SET8 binding site was analyzed in esophageal squamous cell carcinoma (ESCC) patients, the SET8 C/C genotype was independently associated with longer post-operative survival by multivariate analysis (relative risk, 2.250; 95% CI, 1.041–4.857; p = 0.039). Moreover, the reduced SET8 expression mediated by SET8 C/C genotype was associated with longer ESCC survival. Functional assay indicated that the SET8 knock down could inhibit proliferation and promote apoptosis of ESCC cells. The subsequent assay also showed the markedly inhibition of ESCC cell migration and invasion by SET8 knock down. Our data suggested that the altering SET8 expression, which is mediated at least partly by miR-502 through changing the binding affinity between miR-502 and SET8 3′ UTR, could modify the ESCC outcome by inhibiting the proliferation and invasion as well as promoting the apoptosis of ECSS cell. Our data indicated that SET8 was a new target for ESCC therapy.

Highlights

SET8 could promote epithelial-mesenchymal transition and confer TWIST dual transcriptional activities thereby to increased metastasis capacity of breast cancer cells[18,19]
We showed firstly that the rs16917496 SNP in the miR-502 binding site of the SET8 3′UTR was associated with esophageal squamous cell carcinoma (ESCC) survival by multivariate analysis; secondly we showed that the SNP resulting in the T to C transition might destroy the G:C bond in miR-502 and SET8 binding site so as to modulate SET8 expression by immunostaining and luciferase reporter assays; thirdly we showed that SET8 expression was associated with ESCC outcome; we showed that the reduced SET8 could inhibit proliferation and invasion as well as increase apotosis for ESCC cell of Eca[109]
We assessed the role of SET8 knockdown on ESCC cell of TE1 referring to proliferation, invasion and apoptosis, the same results was obtained as it do in Eca[109] cells

Summary

Introduction

SET8 could promote epithelial-mesenchymal transition and confer TWIST dual transcriptional activities thereby to increased metastasis capacity of breast cancer cells[18,19]. We found the rs16917496 SNP including C/C, C/T and T/T genotypes in the “seed” region of SET8 3′UTR where miR-502 binding was associated with both cancer risk of epithelial ovarian cancer and outcome of hepatocellular carcinoma, small cell lung cancer and non-Hodgkin’s lymphomas[20,21,22,23]. We genotyped this SNP in ESCC patients in a case-control study to assess its relationships to cancer risk and outcome

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Results

Conclusion