Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

DEAD-box RNA helicase DDX20 in redox-dependent regulation of Wnt/β-catenin signalling in triple-negative breast cancer (#221)

Sebastian Pohl 1 , Mark Agostino 1 , Shazib Pervaiz 2 , Alan Prem Kumar 3 , Arun Dharmarajan 1
  1. School of Biomedical Sciences, Curtin University, Perth, W.A, Australia
  2. Department of Physiology, National University of Singapore, Singapore
  3. Cancer Science Institute, Singapore

DEAD-Box helicase DDX20 is a multifunctional regulatory protein that has been implicated in numerous signalling pathways. Recently, we reported DDX20 is highly expressed and a driver of the aggressiveness and invasive phenotypes commonly associated with the basal-like or triple-negative breast cancer (TNBC) subtype. Interestingly, these subtype of tumours have been shown to have high Wnt activity. Our aim was to investigate the mechanisms of redox regulation by DDX20 and Wnt signalling in triple-negative breast cancer. Our study demonstrates an essential role for DDX20 in the regulation of Wnt/β-catenin signalling, whereby TNBC cell lines depleted of DDX20 showed impaired Wnt signalling through decreased levels of active b-catenin albeit in the presence of Wnt3a stimulation. DDX20 depleted cells exhibited a greater sensitivity to chemotherapeutic agents. Our data propose that the mode of cell death may be a result of DDX20-induced changes in the intracellular H2O2 levels. The changes in the intracellular redox milieu decrease Wnt/b-catenin signalling, with concomitant downregulation of Wnt target genes, AXIN2, LEF1 and TCF7L2 (TCF4). Mechanistically we demonstrate intracellular redox levels are controlled through Wnt signalling mediated catalase and MnSOD gene expression via recruitment of TCF4 to the promoter region of the MnSOD and intron 1 of the catalase gene. Together, these data demonstrate a new role for DDX20 and Wnt signalling in the regulation of redox-dependent cell fate and a shift from the current paradigm that b-catenin transcription of redox-regulatory genes are generally governed by forkhead transcription (FOXO) factors.