Diana was awarded 2nd Prize in the 2012 Johnson & Johnson Asia Outstanding Graduate Thesis Award in Bio-tech, a highly competitive international award. She is one of two students from NUS who won the award.
“JJSI Asia Outstanding Graduate Thesis Award in Bio-tech” is an annual award sponsored by Johnson & Johnson Corporate Office of Science and Technology ( COSAT, www.jnjcosat.com/cosat ). The award aims to promote and recognize the best graduate students in Asia who have made significant contributions in the field of bio-tech related to life sciences.
Title of Thesis: DEAD-box helicase DP103, an novel essential regulator of NEMO SUMOylation and NFκB activation, defines the metastatic potential of human breast cancers
Despite advances, 20% to 30% of patients with early breast cancers experience relapse with distant metastasis. Therefore, there is a pressing need to identify new markers and therapeutic targets for metastatic breast cancers. In this report we identify the DEAD-box helicase, DP103, as a novel prognostic marker that predicts and mediates metastasis of human breast cancers. Furthermore, we identify the molecular mechanism underlying this novel hitherto unidentified role of this helicase. We show that DP103's function in breast cancers is attributable to its ability to elevate the levels of matrix metalloproteinase MMP9 through the activation of the well characterized oncogenic transcription factor NFκB. We further delineate that activation of NFκB by DP103 depends on its ability to function as a positive cofactor for the SUMO conjugating enzyme PIASy, an enzyme necessary for SUMOylating NEMO, an essential component of NFκB signaling.
Figure Legend: Model of DP103 regulation in NFκB pathway under genotoxic stress
In normal or low invasive cancer cells, low expression of DP103 does not affect the normal reversible SUMOylation and deSUMOylation of NEMO upon genotoxic stress. However, the presence of high DP103 in highly invasive tumors enhanced NEMO SUMOylation through increased recruitment of PIASy to the substrate NEMO, and at the same time by reducing the interaction of NEMO with the SUMO protease SENP2. These resulted in a constitutive activation of NFκB which accounts for the elevated levels of its associated metastatic genes like MMP9 and confers protection against apoptosis.
For more information on Vinay TERGAONKAR’s laboratory, please click here.