Advisor(s)
Susan Bellis
Committee Member(s)
Alexa Mattheyses
Chenbei Chang
Sasanka Ramanadham
Selvarangan Ponnnazhagan
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
1-7-2025
Abstract
Abnormal glycosylation has long been identified as a key feature of cancer. Aberrant glycan structures on tumor cells arise from the dysregulation of select glycosyltransferases. For example, sialyltransferase ST6GAL1 is notable for its high expression in various cancers, including breast, colon, ovarian, and pancreatic. ST6GAL1 introduces α2-6-linkage sialylation to N-glycans on proteins, endowing cancer cells with stem cell-like properties. This modification contributes to resistance to apoptosis mediated by death receptors like TNFR1. Despite its significance in cancer, the regulatory mechanisms controlling ST6GAL1 expression remain largely unexplored. Additionally, it is unclear whether the apoptosis-resistant effect of sialylation is caused by an increase in the overall levels of sialic acid or is a specific function of α2-6 sialylation. In this dissertation, we explored 1) the mechanism by which ST6GAL1-mediated sialylation modulates death receptor dynamics and cell fate and 2) the regulation of the crucial enzyme ST6GAL1 in both normal and cancer cells. For the role of ST6GAL1 in TNFR1 signaling, we focused on the distinct roles of specific sialylation (α2-3 vs. α2-6) in TNFR1-associated apoptosis. TNFR1 is unique in its ability to determine cell fate by either promoting survival when on the membrane or inducing death upon internalization. This dual effect hinders the success of TNF-related therapies in cancer clinical trials, making it crucial to understand the mechanisms that direct TNFR1 signaling. Our findings revealed that α2-6 sialylated TNFR1 impedes TNF-independent clustering and delays TNF-induced internalization, thereby reducing apoptosis. In the second part, we elucidated the current understanding of ST6GAL1 regulation under physiological and pathological conditions, including studies on ST6GAL1 isoforms and promoters in normal and cancer cells, as well as epigenetic regulation, and post-transcriptional and post-translational controls. Understanding ST6GAL1 regulation could lead to new strategies for targeting ST6GAL1 expression levels in cancer or other diseases. Our novel insights suggest that specific sialoglycan structures on TNFR1 can dictate cell fate, influencing whether a cell survives or undergoes apoptosis. Furthermore, this finding that α2-6 sialylation of TNFR1 diverts signaling toward survival proposes a new therapeutic target to harness the TNFR1 network to induce specific desired outcomes, such as cancer cell death.
ProQuest ID
Recommended Citation
Hwang, Jihye, "Sialylation Of Tnfr1 By St6Gal1 Modulates Receptor Dynamics And Determines Cell Fate" (2025). All ETDs from UAB. 7240.
https://digitalcommons.library.uab.edu/etd-collection/7240
