All ETDs from UAB

Advisory Committee Chair

Anita Hjelmeland

Advisory Committee Members

Susan Bellis

Jonathan E McConathy

Louis Burt Nabors

Karina Yoon

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences


Glioblastoma (GBM) is a rare but deadly cancer with median survival of just 15 months despite of aggressive treatment. Advancement in novel treatment modalities is hindered by its heterogeneous nature, which includes subsets of neural stem cell-like brain tumor initiating cells (BTICs) that are highly tumorigenic and therapy-resistant. bgalactoside a-2,6-sialyltransferase 1 (ST6Gal1) is elevated in most tumors including in normal and neoplastic stem cells. ST6Gal1 imparts oncogenic phenotypes such as invasion, apoptosis evasion, therapy resistance, TIC maintenance among others via sialylation of critical receptors like, Fas, TNFR1, EGFR and more. Yet ST6Gal1 led regulation of BTIC specific cell surface proteins remain uninvestigated. ST6Gal1 expression was elevated in BTICs and high α2,6 sialylation level in GBM PDXs exhibited increased BTIC phenotypes: enhanced self-renewal capacity, elevated in vitro and in vivo growth. More specifically, targeting ST6Gal1 in GBM PDXs led to decreased BTIC characteristics. Further investigation of molecular basis for the observed BTICs phenotypes through proteomics analysis revealed that ST6Gal1 knockdown downregulated important TIC regulators like ALCAM, NRP1 and PDGFRb which were also a2,6-sialylated. Targeting ST6Gal1, significantly reduced the a2,6-sialylation of PDGFRb. When ST6Gal1 knockdown and non-targeting controls were treated with PDGF-BB, p-PDGFRb diminished with ST6Gal1 knockdown. Another factor known to promote TIC maintenance iv is metabolic plasticity. However, the relationship between cell surface protein modification to TIC maintenance and metabolism, particularly regarding sialylation and GBM remains largely unknown. To increase glycolytic metabolism, BTICs upregulate Glucose transporter 3 (GLUT3) which has affinity for glucose and is elevated in BTICs. N-glycosylation of GLUTs is known to regulate GLUT function, but the role of ST6Gal1 in glycolytic metabolism or GLUT activity remains uninvestigated. In Seahorse assays, α2,6 sialylationhigh cells displayed high glycolysis and glycolytic capacity. Further, α2,6 sialylationhigh cells showed increased glucose uptake capacity that decreased with removal of α2,6 sialylation. Similarly, targeting ST6Gal1 expression also diminished the BTIC glucose uptake. Further, knockdown of ST6Gal1 decreased GLUT3 protein expression. Finally, GLUT3 was present in the SNA pull down, hinting GLUT3 as a substrate of ST6Gal1. Together, our findings implicate ST6Gal1 as a central player GBM BTIC maintenance and metabolism through sialylation of important TIC regulators.



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