Preparing for climate change on marine systems in Australia and India.

Australia and India have coastal marine waters warming at a rate faster than 90% of the world’s oceans. Both countries have extensive coastlines and marine jurisdictions with the majority of the population living adjacent to the coast (Box 1). Marine industries play important roles in sustaining the livelihoods of people in coastal rural towns. Increasing food production, minimising carbon emissions and prioritising carbon sequestration opportunities are key issues facing both countries and form the basis of this research plan. In addressing these issues India and Australia are well placed to become leaders in the development of adaptation options, and pioneers of transformational industries

Inhibiting the Hexosamine Biosynthetic Pathway Lowers OGlcNAcylation Levels and Sensitizes Cancer to Environmental Stress

The amounts of the intracellular glycosylation, O-GlcNAc modification, are increased in essentially all tumors when compared to healthy tissue, and lowering O-GlcNAcylation levels results in reduced tumorigenesis and increased cancer cell death. Therefore, the pharmacological reduction of O-GlcNAc may represent a therapeutic vulnerability. The most direct approach to this goal is the inhibition of O-GlcNAc transferase (OGT), the enzyme that directly adds the modification to proteins. However, despite some recent success, this enzyme has proven difficult to inhibit. An alternative strategy involves starving OGT of its sugar substrate UDP-GlcNAc by targeting enzymes of the hexosamine biosynthetic pathway (HBP). Here, we explore the potential of the rate-determining enzyme of this pathway, glutamine fructose-6-phosphate amidotransferase (GFAT). We first show that CRISPR-mediated knockout of GFAT results in inhibition of cancer cell growth in vitro and a xenograft model that correlates with O-GlcNAcylation levels. We then demonstrate that pharmacological inhibition of GFAT sensitizes a small panel of cancer cells to undergo apoptosis in response to diamide-induced oxidative stress. Finally, we find that GFAT expression and O-GlcNAc levels are increased in a spontaneous mouse model of liver cancer. Together these experiments support the further development of inhibitors of the HBP as an indirect approach to lowering O-GlcNAcylation levels in cancer