Effects of a single transient transfection of Ten-eleven translocation 1 catalytic domain on hepatocellular carcinoma.

Yuying Liu,Jiejie Zhan,Jianwu Ding,Hui Zhu,Bin Wen,Pengfei Yi,Fanglin Zhang,Xing Li,Dongyuan Yao,Zhenxue Zhang,Ru Jiang,Changchun Tu,Jiaping Hu,Liping Jiang,Qian Tao

doi:10.1371/journal.pone.0207139

Abstract

Tumor suppressor genes (TSGs), including Ten-eleven translocation 1 (TET1), are hypermethylated in hepatocellular carcinoma (HCC). TET1 catalytic domain (TET1-CD) induces genome-wide DNA demethylation to activate TSGs, but so far, anticancer effects of TET1-CD are unclear. Here we showed that after HCC cells were transiently transfected with TET1-CD, the methylation levels of TSGs, namely APC, p16, RASSF1A, SOCS1 and TET1, were distinctly reduced, and their mRNA levels were significantly increased and HCC cells proliferation, migration and invasion were suppressed, but the methylation and mRNA levels of oncogenes, namely C-myc, Bmi1, EMS1, Kpna2 and c-fos, were not significantly change. Strikingly, HCC subcutaneous xenografts in nude mice remained to be significantly repressed even 54 days after transient transfection of TET1-CD. So, transient transfection of TET1-CD may be a great advance in HCC treatment due to its activation of multiple TSGs and persistent anticancer effects.

Highlights

Hepatocellular carcinoma (HCC) is one of the most malignant tumors with an increasing incidence and mortality rate [1]
Given that tumor suppressor genes (TSGs) promoter CpG islands are extensively hypermethylated [9, 10] and Ten-eleven translocation 1 (TET1)-catalytic domain (CD) induces genome-wide DNA demethylation while full length TET1 does not [26], TET1 catalytic domain (TET1-CD) was transfected into SMMC 7721 cells to verify whether it activates the hypermethylated endogenous TET1 and other TSGs
Compared with expression of oncogenes, expression of TSGs was drastically increased. These results suggest that TET1-CD can exert anticancer activity through its role on activation of TSGs but not through its inhibition of oncogenes

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most malignant tumors with an increasing incidence and mortality rate [1]. Ideal drugs for HCC treatment are lacking due to multi-drug resistance and liver toxicity of systemic chemotherapeutic drugs [2]. It is urgently required to find a more effective way for HCC treatment. HCC initiation and progression are triggered by multiple factors, which include hepatitis B and C virus infection, chronic alcohol consumption, non-alcoholic fatty liver disease, and cirrhosis. The fundamental mechanism of carcinogenesis has long been recognized as activation of oncogenes and/or deactivation of tumor suppressor genes (TSGs) [3], which are closely related to demethylation and hypermethylation, respectively [4,5,6,7,8]. Hypermethylation of TSG promoter CpG islands is a ubiquitous phenomenon in human tumors [9, 10]

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Results

Conclusion