Download Disruption of FAT10–MAD2 binding inhibits tumour progression

Disruption of FAT10–MAD2 binding
inhibits tumour progression
Steven Setiawan Theng, Wei Wang, Way-Champ Mah, Cheryl Chan, Jingli Zhuo, Yun Gao, Haina
Qin, Liangzhong Lim, Samuel S. Chong, Jianxing Song, and Caroline G. Lee
FAT10 is a molecule that is found at low levels in various tissues of the body. Its expression
level is significantly increased during inflammation and in various inflammation-associated
cancers including hepatocellular carcinoma (HCC) and colorectal cancer (CRC).
Our
laboratory previously found that over-expression of FAT10 promotes tumor formation, growth
and progression. We also discovered that FAT10 interacts with a protein called MAD2, which
serves as a gatekeeper of cell-division to ensure that each cell receives the same number of
chromosomes. When FAT10 binds to MAD2, it pulls MAD2 away from its gate-keeping
function, causing many cells to carry abnormal number of chromosomes leading to cancer.
In this study, in collaboration with A/Prof Song Jianxing, we determined the three-dimensional
structures of FAT10 using the state-of-the-art nuclear magnetic resonance (NMR)
spectroscopy, and further examined the relationship between the two proteins. Using genetic
mutation manipulation, we discovered that when the binding between FAT10 and MAD2 is
specifically disrupted without affecting FAT10’s interaction with its other known key
interaction partners, the number of chromosomes in the affected cells is restored and tumour
progression is curtailed.
Our findings present a new paradigm for drug targeting and pave the way for the development
of a novel small-molecule anti-cancer inhibitor targeting the specific interaction between
FAT10 and MAD2. Many current strategies target over-expressed genes to inhibit their
expression. As many of these cellular genes also perform other physiological functions in
addition to causing cancer, inhibiting their expression in a blanket fashion may result in
undesirable side effects as the physiological function of these genes may be affected as well.
Our strategy works differently as it targets a specific pathological function of the ‘culprit’
molecule without affecting its other physiological functions. This is especially important for a
molecule like FAT10 which is not only over-expressed during cancer formation but is also
over-expressed during immune response.
------------------------------------------------------------------------------------------------------------------------The full paper can be accessed via:
http://www.pnas.org/content/111/49/E5282.abstract
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