PROJECT SUMMARY/ABSTRACT
One of the least-investigated areas of research in brain pathologies is glycosylation, which is a critical regulator of
cell surface protein structure and function. ST6Gal1 is the primary enzyme that a2,6 sialylates N-glycosylated
proteins destined for the plasma membrane or secretion. Sialylation adds a negatively-charged, sialic acid to the
end of an oligosaccharide chain of a glycoprotein. Sialylation of distinct protein subsets has important effects on
conformation, clustering and cell surface retention as has been found for some integrins, growth factor receptors
and death receptors. Through this mechanism, ST6Gal1 regulates phenotypes including survival, invasion, and
stem cell maintenance. However, there are critical gaps in our understanding of how ST6Gal1-mediated sialylation
impacts brain tumor cell growth or differentiation state, and there are no studies identifying a2,6 sialylated proteins
or ST6Gal1 regulated pathways in brain tumors. Our preliminary data demonstrate a novel, pro-tumorigenic role for
a2,6 sialylation and ST6Gal1 in the deadly brain tumor glioblastoma. We seek to determine whether ST6Gal1-
mediated a2,6 sialylation promotes brain tumor initiating cell maintenance and metabolic plasticity. In the short-
term, our results will lead to an improved understanding of how ST6Gal1-mediated a2,6 sialylation regulates protein
expression and function to impact brain tumor propagation. In the long-term, these studies may offer the potential
for new mechanisms of therapeutic intervention for the treatment of brain tumors as ST6Gal1 inhibitors are under
development.
