ELUCIDATION OF THE ROLE OF FAT10 IN TUMORIGENESIS

Abstract

FAT10 (human leukocyte antigen F-associated transcript 10) is an 18kDA protein, which consists of 165 amino acid residues. It belongs to the ubiquitin-like modifier (UBL) family of proteins and encompasses two ubiquitin-like domains in tandem array. Since Ubiquitin is known to be involved in tumorigensis, we hypothesized that FAT10 as an ubiquitin-like protein also played a role in tumorigensis, since FAT10 has been reported to be overexpressed in several cancers, including colorectal cancer. However, it remains unclear whether FAT10 plays a casual role in driving the malignancy of colorectal cancer, and if so, what the mechanisms involved were. Therefore, this study aimed to address the role of FAT10 in promoting the malignancy of colorectal cancer cells as well as to uncover the mechanism underlying FAT10¿s role in driving tumorigensis. Collectively, our results demonstrated the pro-malignancy functions of FAT10 in inducing cell proliferation, invasion and tumor growth in both colorectal cancer cells as well as non-tumorigenic immortalized hepatocytes.

This thesis also highlighted Mad2-binding as an important mechanism by which FAT10 exerts its effect on cell malignancy. Therefore, based on our collective data, we have demonstrated that FAT10 exerts its pro-malignancy effects through disruption of mitotic spindle checkpoint via interaction with Mad2.

In conclusion, we have demonstrated that FAT10 plays an important role in tumorigenesis and cell malignancy, consistent with the reports of FAT10 overexpression in human tumor samples and we demonstrated that disruption of FAT10 and Mad2 binding significantly resulted in tumor regression and reduced cell malignancy. Our findings have unraveled FAT10 as a crucial determinant of malignant cellular behaviors as well as its potential role as a therapeutic target in cancers.