Investigating the Promoter of FAT10 Gene in HCC Patients.

Yu Jin,Dongwei Zhang,Guangyi Wang,Jingbo Wang,Shuaichen Liu,Caroline G L Lee

doi:10.3390/genes9070319

Abstract

FAT10, which is also known as diubiquitin, has been implicated to play important roles in immune regulation and tumorigenesis. Its expression is up-regulated in the tumors of Hepatocellular Carcinoma (HCC) and other cancer patients. High levels of FAT10 in cells have been shown to result in increased mitotic non-disjunction and chromosome instability, leading to tumorigenesis. To evaluate whether the aberrant up-regulation of the FAT10 gene in the tumors of HCC patients is due to mutations or the aberrant methylation of CG dinucleotides at the FAT10 promoter, sequencing and methylation-specific sequencing of the promoter of FAT10 was performed. No mutations were found that could explain the differential expression of FAT10 between the tumor and non-tumorous tissues of HCC patients. However, six single nucleotide polymorphisms (SNPs), including one that has not been previously reported, were identified at the promoter of the FAT10 gene. Different haplotypes of these SNPs were found to significantly mediate different FAT10 promoter activities. Consistent with the experimental observation, differential FAT10 expression in the tumors of HCC patients carrying haplotype 1 was generally higher than those carrying haplotype II. Notably, the methylation status of this promoter was found to correlate with FAT10 expression levels. Hence, the aberrant overexpression of the FAT10 gene in the tumors of HCC patients is likely due to aberrant methylation, rather than mutations at the FAT10 promoter.

Highlights

FAT10, which is sometimes referred to as diubiquitin, was initially identified as one of the genes at the major histocompatibility complex locus in human chromosome 6 [1]
Since FAT10 is aberrantly overexpressed in the tumors of Hepatocellular Carcinoma (HCC) and other cancer patients [15], this study aims to evaluate whether the dysregulation of FAT10 expression in the tumor tissues of this study aims to evaluate whether the dysregulation of FAT10 expression in the tumor tissues of patients atthe theFAT10
To evaluate whether mutations/polymorphisms at the FAT10 promoter could account for the aberrant overexpression of FAT10 in the tumors of HCC patients, we sequenced approximately 1.3 kb of the FAT10 promoter in the tumor, and paired non-tumorous tissues from 37 Chinese HCC patients and 39 normal healthy Chinese individuals of a similar age

Summary

Introduction

FAT10, which is sometimes referred to as diubiquitin, was initially identified as one of the genes at the major histocompatibility complex locus in human chromosome 6 [1]. It is an 18 kDa protein and belongs to the ubiquitin-like modifiers (UBLs) family of proteins sharing 29% and 36% identity with ubiquitin at the N-terminus and C-terminus, respectively. FAT10 was suggested to function in a similar way as ubiquitin [2], in that it can act as a proteinaceous tag and target proteins for degradation by the 26S proteasome via attaching itself to that protein [3]. Unlike ubiquitin, which is recycled from the degraded target proteins, FAT10 was reported to be degraded together with its target, resulting in a relatively short half-life [3]

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