INVESTIGATING THE TUMOUR SUPPRESSING ROLE OF HACE1 AND ITS NOVEL CONTRIBUTION TO CARDIAC DEVELOPMENT USING THE ZEBRAFISH MODEL

Abstract

HACE1 is an E3 ubiquitin-ligase that is epigenetically downregulated in various malignancies. The mechanisms underlying its role in tumourigenesis and in normal vertebrate development have not been well elucidated. We found that loss of hace1 in zebrafish via morpholino knockdown results in higher expression of gamma H2AX, a marker of double stranded DNA breaks, as well as increased levels of the reactive oxygen species (ROS) hydrogen peroxide (H2O2), which was rescued by treatment with NADPH oxidase inhibitors as well as genetic inhibition of the rac1-dependent components of this complex. hace1 morphants demonstrated an increased incidence of cardiac deformities and increased expression of rac1. These cardiac phenotypes appear to be regulated by rac1-dependent NADPH pathway components. Our data reveal a molecular mechanism of HACE1 both in cancer and normal cardiac development, and thus constitutes the first known example of a tumour suppressor that regulates a developmental process via ROS-dependent mechanisms.