All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

David A Schneider

Douglas R Hurst

Daniel C Bullard

Nabiha Yusuf

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

ST6Gal-I is a sialyltransferase that functions to add an 2-6 linked sialic acid to N-linked glycoproteins. The expression of ST6Gal-I is upregulated in many cancers at both the mRNA and protein levels. ST6Gal-I has also been shown to promote cancer stem cell (CSC) characteristics including chemoresistance, tumor-initiating potential, and spheroid growth. However, the transcriptional drivers of ST6Gal-I expression in stem-like cells remain largely unknown. Herein we highlight that SOX2 and ST6GAL1 are both located on one of the most commonly amplified chromosomal segments in cancer, amplicon 3q26. Copy number gains in both SOX2 and ST6GAL1 are observed in roughly 25% of an ovarian cancer cohort available through the The Cancer Genome Atlas (TCGA) database. Amplification of 3q26 is associated with poor patient prognosis, increased aggressiveness of disease, and chemotherapeutic resistance. We identified that Sox2 and ST6Gal-I are co-expressed across a range of ovarian cancer cell lines and found a strong correspondence between their copy number gains in cell lines available from the NCI-60 (National Cancer Institute) panel of 60 human cancer cell lines. In addition to being genetically co-amplified, Chromatin Immunoprecipitation (ChIP) assay suggest that Sox2 binds regions proximal to the P3 promoter of ST6Gal-I to promote its transcription. Using ovarian cancer cell model systems, we forced overexpression (OE) or knockdown (KD) of Sox2, and consistently found that high expression of Sox2 directly induces expression of ST6Gal-I. In cells with Sox2 OE, ST6Gal-I mRNA and protein levels rise, and there is an increase in overall 2-6 surface sialylation, as measured by sambucus nigra agglutinin (SNA) labelling. Contrarily, Sox2 KD causes a decrease in ST6Gal-I mRNA and protein, as well as surface 2-6 sialylation. These collective studies identify Sox2 as a potent driver of ST6Gal-I and highlight novel mechanisms regulating ST6Gal-I expression.

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