Decrease of 5-Hydroxymethylcytosine Is Associated with Progression of Hepatocellular Carcinoma through Downregulation of TET1

Abstract

DNA methylation is an important epigenetic modification and is frequently altered in cancer. Convert of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5 hmC was altered in various types of cancers. However, the change of 5 hmC level in hepatocellular carcinoma (HCC) and association with clinical outcome were not well defined. Here, we reported that level of 5 hmC was decreased in HCC tissues, as compared with non-tumor tissues. Clincopathological analysis showed the decreased level of 5 hmC in HCC was associated with tumor size, AFP level and poor overall survival. We also found that the decreased level of 5 hmC in non-tumor tissues was associated with tumor recurrence in the first year after surgical resection. In an animal model with carcinogen DEN-induced HCC, we found that the level of 5 hmC was gradually decreased in the livers during the period of induction. There was further reduction of 5 hmC in tumor tissues when tumors were developed. In contrast, level of 5 mC was increased in HCC tissues and the increased 5 mC level was associated with capsular invasion, vascular thrombosis, tumor recurrence and overall survival. Furthermore, our data showed that expression of TET1, but not TET2 and TET3, was downregulated in HCC. Taken together, our data indicated 5 hmC may be served as a prognostic marker for HCC and the decreased expression of TET1 is likely one of the mechanisms underlying 5 hmC loss in HCC.

Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer

“…Recent studies revealed that TET1 protein has a potential mechanism related to DNA demethylation and may play an important role in transcriptional regulation of genes involved in basic housekeeping processes and those regulating differentiation and development (8,26,30). Dysregulation of the TET1 gene has been found in many types of cancers and appears to be associated oncogenic processes in solid tumor tissues, such as colon, prostate, breast, and hepatocellular cancers (22,(31)(32)(33). Suppression of TET1 promotes tumor cell invasion and correlated with poor survival outcomes in breast cancer patients (22).…”

Epigenetically modified nucleotides in chronic heroin and cocaine treated mice

“…Indeed, decreased 5-hmC has been associated with hepatocellular carcinomas and downregulation of the expression of TET1 proteins, with tumor size and poor survival and with alpha-fetoprotein levels (Liu et al, 2013). Moreover, Ivanov et al (Ivanov et al, 2013) suggest that 5-hmC plays a role in liver function and development and that it might be responsible for inter-individual differences in drug metabolism and toxicity.…”

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…This loss of 5hmC in genomic context may lead to gene body hypermethylation as observed in kidney cancer and can hypermethylate promoters of tumor suppressor genes (TSG) that are frequently observed in cancers [24]. Reduced 5hmC is a predictive marker for poor prognosis and survival for multiple cancers like breast, astrocytoma, laryngeal squamous cell carcinoma, renal, oesophageal, gastric and hepatocellular carcinoma (HCC) [24][25][26][27][28][29][30]. Moreover, mutations in TET2 are frequently observed with decrease in 5hmC in hematological cancers, additionally mutations of 5hmC regulating enzymes like IDH1/2, SDH and FH were also observed [19,20,31,32].…”