Investigating the Role of TCF7L1 in Colorectal Cancer
Restricted (Penn State Only)
- Author:
- King, Carli
- Graduate Program:
- Biomedical Sciences (PHD)
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- December 07, 2023
- Committee Members:
- Gregory Yochum, Chair & Dissertation Advisor
Zhonghua Gao, Major Field Member
Kristin Eckert, Major Field Member
Lisa Shantz, Program Head/Chair
Vladimir Spiegelman, Outside Unit & Field Member - Keywords:
- colorectal cancer
TCF7L1 - Abstract:
- Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States and the second leading cause of cancer-related deaths globally. Mutations in key components of the Wnt/β-catenin signaling pathway drive CRC, in part, by deregulating expression of genes controlled by the T-cell factor (TCF) family of transcription factors. TCFs contain a highly conserved DNA binding domain that mediates association with TCF binding elements (TBEs) within Wnt-responsive DNA elements (WREs). Of the four TCF family members, transcription factor 7 like 1 (TCF7L1) predominantly functions as a transcriptional repressor. Despite TCF7L1 being attributed an oncogenic role in CRC, only a limited number of target genes whose expression it directly regulates in this cancer have been characterized. Here, we aimed to further define the role of TCF7L1 as a repressor of Wnt target gene expression in CRC cells with constitutively active Wnt/β-catenin signaling. Using molecular biology and biochemical assays, we demonstrate that TCF7L1 represses expression of intestinal stem cell marker, leucine-rich-repeat containing G-protein-coupled receptor 5 (LGR5), through a novel promoter-proximal WRE at the LGR5 locus. Furthermore, a combination of RNA- and chromatin immunoprecipitation (ChIP)-sequencing identified additional TCF7L1-regulated target genes in CRC. Using these data sets, we noted enrichment for genes associated with epithelial-mesenchymal transition (EMT) and defined a role for TCF7L1 in promoting CRC cell migration, invasion, and adhesion in vitro. These phenotypes were mediated, in part, through TCF7L1 repression of growth arrest specific 1 (GAS1). These findings uncovered two novel target genes, LGR5 and GAS1, whose expression is directly regulated by TCF7L1 in CRC. Additionally, we define a novel role for TCF7L1 in promoting EMT-associated phenotypes in CRC. Together, our studies describe a new mechanism by which TCF7L1 contributes to intrinsic cellular plasticity and tumor heterogeneity.