Congratulations to Cai Wanpei, CSI graduate student of Dr Alan Prem Kumar’s group, for being a recipient of the EMBO Travel Grant awarded by the EMBO Conference Wnt 2016. This meeting is an annual international conference that aims to provide a platform for scientists from all over the world to exchange their latest results and discuss new ideas and concepts on Wnt signal transduction. For this year’s meeting, it was held in Brno, Czech Republic from 14-17 September 2016.
Wanpei’s abstract was selected amongst 150 abstracts to be awarded this EMBO Travel Grant. Her work, which is a collaboration with several principal investigators at CSI Singapore and Duke-NUS Medical School, describes DEAD-box RNA helicase DDX20 as a novel driver of Wnt/β-catenin pathway in triple negative breast cancer.
Wnt-DDX20-GSK3β Cascade Promotes Wnt/β-catenin Signaling in Parental and Stem Cells from Triple Negative Breast Cancer
Wanpei Cai1,2, Sebastian Pohl3, Mark Agostino3, Arunasalam M. Dharmarajan3, Celestial T. Yap4, Henry Yang1, Louis Gaboury5 , Gautam Sethi2, Takaomi Sanda1, Peter E. Lobie1,2, David M. Virshup6,7, Alan Prem Kumar1,2,3,8
1Cancer Science Institute of Singapore, National University of Singapore; 2Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore; 3School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Western Australia; 3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore; 5Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal; 6Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore; 7Cancer & Stem Cell Biology Program, Graduate Medical School, Duke-NUS; 8Department of Biological Sciences, University of North Texas, Denton, TX, USA
Breast cancer is a principle cause of death in women globally and a diverse malignancy. Despite recent advances in breast cancer therapeutics, mortality of highly metastatic triple negative breast cancer (TNBC) subtype remains high; due to their lack hormone receptors expression for targeted therapy. Therefore, there is a pressing need to identify new prognostic markers and therapeutic targets for this group of breast cancers. Aberrant activation of Wnt/β-catenin signaling has been associated with breast cancers; where 40% of total breast cancers have elevated β-catenin levels and/or Wnt activity. Herein, we identify DEAD-box RNA helicase DDX20 as a novel driver of Wnt/β-catenin pathway in TNBC. The link between DDX20 and Wnt/β-catenin signaling was further validated using in vivo Zebrafish models, where disruption in DDX20 gene splicing mechanisms resulted in severe early embryonic developmental defects such as reduced brain size, tail defects, lack of melanophores formation and cardiac deformities, which phenocopies loss of Wnt/β-catenin signaling during gastrulation. Interestingly, we also show DDX20 drives breast cancer stem cell (CSC) formation, a process regulated by the Wnt/β-catenin pathway. Depletion of DDX20 led to a marked reduction in the percentage of CSC-enriched mammospheres with reduced tumor-initiating ability. Mechanistically, we show DDX20’s role in driving Wnt/β-catenin pathway is independent of caesin kinase I activity but highly dependent on GSK3β activity. More interestingly, from molecular docking data, we found DDX20 protein has to be phosphorylated at threonine residue 552, when it interacts with GSK3β. Surprisingly, induction of Wnt/β-catenin signaling also significantly increased DDX20 expression, indicating a possible positive feedback loop. Collectively, our data suggest a novel regulatory role of DDX20 in the Wnt/β-catenin signaling pathway in parental and CSC derived TNBC. Breaking the Achilles’ heel of this positive feedback loop and thereby weaken Wnt/β-catenin activity, we aim to achieve a much favorable outcome in TNBC patients.