All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Etty Benveniste

Kevin Kirk

Jay M McDonald

Danny Welch

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The golgi glycosyltransferase, ST6Gal-I, adds a negatively-charged sialic acid in an alpha-2-6 linkage to N-linked glycans. ST6Gal-I is upregulated in many cancers, and is associated with increased metastasis and poor patient prognosis. ST6Gal-I expression has been shown to be driven by oncogenic-ras signaling. However, mechanistic details of the role ST6Gal-I plays in tumor initiation and progression are not well defined. Historically, studies have focused on contributions of ST6Gal-I to the malignant cell phenotypes of migration and invasion. Emerging evidence including studies contained in this dissertation have begun to elucidate a role for ST6Gal-I as a regulator of apoptotic signaling by providing protection against apoptotic stimuli. Additionally, we have found ST6Gal-I to be a potential regulator of stem cell populations in normal and cancer tissues. Our work establishes the Fas receptor as a target for ST6Gal-I alpha-2-6-linked sialylation and shows that this sialylation confers protection against Fas-mediated apoptosis. In both knockdown and forced expression cell models we demonstrated that ST6Gal-I protected cells from apoptosis as evidenced by decreased cleavage of caspases 3 and 8, and decreased morphological markers of apoptosis including nuclear condensation. Mechanistically, we found Fas sialylation blocked two vital steps of Fas-mediated apoptotic signaling, DISC formation and receptor internalization. Furthermore, we found ST6Gal-I upregulation resulted in hypersialylation of the Fas receptor in human colon tumors. In addition to studies regarding functional outcomes of ST6Gal-I sialylation, we have begun to delineate ST6Gal-I protein expression and localization in several human epithelial tumors, including colon, prostate, ovarian, and pancreatic cancers. We have shown ST6Gal-I protein expression is upregulated in 14/15 colon carcinomas assayed, with highly upregulated staining in a majority of epithelial cells within immunostained tumors. ST6Gal-I expression appeared to localize to stem cell compartments within both normal colon and normal epidermal tissues and was also found to be upregulated in iPS cells. Additionally, cancer stem cell enrichment correlated with ST6Gal-I expression in two independent cell models. This dissertation provides evidence regarding the role of ST6Gal-I in tumorigenesis and protection against apoptosis, and also raises the intriguing possibility that ST6Gal-I may contribute to tumor initiation through the regulation of stem cell phenotypes.

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