Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers

Abstract

The ubiquitin-like modifier (UBL) family has recently generated much interest in the scientific community, as it is implicated to play important regulatory roles via novel protein-protein modification. FAT10 (diubiquitin) belongs to this family of proteins, comprising two ubiquitin-like moieties fused in tandem, and has been implicated to be involved in the maintenance of spindle integrity during mitosis. As FAT10 may play a role in the regulation of genomic stability, we examined if there is an association between FAT10 expression and hepatocellular carcinoma (HCC) or other cancers. Northern blot analyses revealed upregulation of FAT10 expression in the tumors of 90% of HCC patients. In situ hybridization as well as immunohistochemistry utilizing anti-FAT10 antibodies localized highest FAT10 expression in the nucleus of HCC hepatocytes rather than the surrounding immune and non-HCC cells. FAT10 expression was also found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system. In conclusion, we demonstrated upregulation of FAT10 expression in various gastrointestinal and gynecological cancers. Its overexpression is unrelated to the general increase in protein synthesis or a general immune/ inflammatory response to cancer. Rather, FAT10 may modulate tumorigenesis through its reported interaction with the MAD2 spindle-assembly checkpoint protein.

The ubiquitin-like modifier FAT10 in cancer development

“…system such as thymus, lymph nodes, fetal liver and spleen (Canaan et al, 2006;Lee et al, 2003;Liu et al, 1999;Lukasiak et al, 2008). The high expression of FAT10 in the thymus could be allocated to medullary thymic epithelial cells (mTECs) and it was shown that FAT10 modifies thymic T-cell selection, probably due to an altered peptide presentation on MHC class I molecules (Buerger et al, 2015).…”

“…FAT10 expression is highly up-regulated in many different cancer types such as colon cancer, hepatocellular carcinoma (HCC), gastrointestinal and pancreatic carcinomas, gynecological carcinomas, and glioma (Lee et al, 2003;Lukasiak et al, 2008;Qing et al, 2011;Sun et al, 2014;Yuan et al, 2012). In liver neoplasia FAT10 is even described as an epigenetic marker (French et al, 2010a,b;Oliva et al, 2008).…”

p53 negatively regulates the expression of FAT10, a gene upregulated in various cancers

“…Dysregulation of MAD2 has also been implicated in tumorigenesis (Michel et al, 2001;Wang et al, 2002;Li et al, 2003). Notably, FAT10 expression was found to be upregulated in hepatocellular carcinoma (HCC) and other gastrointestinal and gynecological cancers (Lee et al, 2003). For a better appreciation of the role of FAT10 in tumorigenesis, we identified and characterized its promoter to understand how the FAT10 gene is regulated or dysregulated.…”

“…As FAT10 was found to interact with MAD2, a mitotic checkpoint protein (Liu et al, 1999), an attractive hypothesis would be that the repression of FAT10 expression by p53 may facilitate the interaction of MAD2 with cdc20 to induce mitotic arrest. During tumorigenesis, p53 may not function appropriately, leading to enhancement of FAT10 gene expression, observed in several different cancers (Lee et al, 2003). More FAT10 interact with MAD2 resulting in the deregulation of mitosis, leading to genome instability and tumorigenesis.…”

“…Role of FAT10 in cell-cycle regulation has been suggested by its ability to bind to MAD2, a spindle checkpoint protein (Liu et al, 1999). We recently reported that the FAT10 gene is upregulated in various cancers (Lee et al, 2003), implicating its role in tumorigenesis.…”