FAT10, an ubiquitin-like protein, confers malignant properties in non-tumorigenic and tumorigenic cells

Abstract

FAT10 (HLA-F-adjacent transcript 10) is an ubiquitin-like modifier, which has been implicated in immune response and cancer development. In particular, the hypothesis of FAT10 as a mediator of tumorigenesis stems from its ability to associate with a spindle checkpoint protein Mad2 during mitosis and cause aneuploidy, a hallmark of cancer cells. Furthermore, FAT10 is overexpressed in several carcinomas types, including that of liver and colon. Nevertheless, direct evidence linking FAT10 to cell malignant transformation and progression is lacking. Here, we demonstrate that high FAT10 expression enhanced the proliferative, invasive, migratory and adhesive functions of the transformed cell line, HCT116. These observations were consistently demonstrated in an immortalized, non-tumorigenic liver cell line NeHepLxHT. Importantly, FAT10 can induce malignant transformation as evidenced from the anchorage-independent growth as well as in vivo tumor-forming abilities of FAT10-overexpressing NeHepLxHT cells, whereas in rapidly proliferating HCT116, increased FAT10 further augmented tumor growth. FAT10 was found to activate nuclear factor-κB (NFκB), which in turn upregulated the chemokine receptors CXCR4 and CXCR7. Importantly, small interfering RNA depletion of CXCR7 and CXCR4 attenuated cell invasion of FAT10-overexpressing cells, indicating that the CXCR4/7 is crucial for the FAT10-dependent malignant phenotypes. Taken together, our data reveal novel functions of FAT10 in malignant transformation and progression, via the NFκB-CXCR4/7 pathway.

The ubiquitin-like modifier FAT10 in cancer development

“…NF-B is a transcription factor with multiple target genes, so the question arises, which are the genes downstream of FAT10 and NF-B? The microarray expression analysis of FAT10 overexpressing NeHepLxHT and HCT116 cells by Gao et al (2014) revealed that the chemokine receptors CXCR4 and CXCR7 were highly up-regulated in FAT10 overexpressing NeHepLxHT cells, consistent with other data showing that NF-B is a transcription factor for both genes (Katoh and Katoh, 2010;Tarnowski et al, 2010). CXCR4 and −7 are both described to promote invasion and tumor growth in several cancer types (Gao et al, 2010;Heinrich et al, 2012;Liang et al, 2005;Zheng et al, 2010).…”

Ubiquitin-like Protein FAT10 Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Modifying β-Catenin Degradation

“…Gao and colleagues (34) reported that high FAT10 expression enhanced the invasive, migratory nature of the transformed cell line and HCT116 via the NF-kB-CXCR4/7 pathway. Another study found that FAT10 promoted the invasion of HCC cells via the Akt/ GSK3b pathway (14).…”

The ubiquitin-like modifier FAT10 decorates autophagy targeted Salmonella and contributes to resistance of mice

“…FAT10 expression is supposed to have proapoptotic functions (Liu et al, 1999;Raasi et al, 2001;Ross et al, 2006), an influence on chromosomal stability and cell cycle regulation (Liu et al, 1999;Ren et al, 2011), NF-kB signaling (Gong et al, 2010) and aggresome formation (Kalveram et al, 2008). In addition, FAT10 has been suggested to have antiapoptotic functions and is implicated in carcinogenesis because it is expressed in various cancer types (Gao et al, 2014;Lee et al, 2003;Lukasiak et al, 2008;Zhang et al, 2006).…”