Advisor(s)
Susan Bellis
Committee Member(s)
Anita Hjelmeland
Jan Novak
Laurie Harrington
Mick Edmonds
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Genetics
Date of Award
1-6-2025
Abstract
The sialyltransferase ST6GAL1 is overexpressed in several cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane proteins, modifying their structure and function. Despite extensive research on how ST6GAL1 affects cell phenotype, the mechanisms regulating its expression remain largely unexplored. In this study, we investigated how two pro-inflammatory cytokines, IL-1β and IL-6, prevalent in the PDAC tumor microenvironment, regulate ST6GAL1 expression. We used the Suit-2 PDAC cell line and its metastatic subclones, S2-013 and S2-LM7AA, to monitor cytokine activity. Treatment with IL-1β or IL-6 increased ST6GAL1 protein and mRNA expression across all cell models. Specifically, IL-1β and IL-6 upregulated the ST6GAL1 YZ mRNA isoform, driven by the P3 promoter, while the H and X isoforms were not detected. Promoter reporter assays confirmed that both cytokines activated transcription from the P3 promoter. Further analysis of downstream signaling mechanisms revealed that IL-1β and IL-6 signal through the NFκB and STAT3 transcription factors, respectively. CUT&RUN experiments showed that IL-1β promotes NFκB binding to the ST6GAL1 P3 promoter, and IL-6 induces STAT3 binding to the same promoter. Furthermore, inhibition of NFκB and STAT3 blocked the cytokine-induced upregulation of ST6GAL1. These findings elucidate a novel molecular pathway by which cytokines in the tumor microenvironment upregulate ST6GAL1 in PDAC cells.
ProQuest ID
Recommended Citation
Silva, Austin David, "St6Gal1 Is Upregulated In Pancreatic Cancer Cells By Pro-Inflammatory Cytokines" (2025). All ETDs from UAB. 7239.
https://digitalcommons.library.uab.edu/etd-collection/7239
