# Dissecting the role of TCF7L1 in colorectal cancer

> **NIH NIH R03** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $158,320

## Abstract

PROJECT SUMMARY
Deregulated Wnt/β-catenin signaling is a common feature of colorectal cancer (CRC), but how this pathway
corrupts target gene expression is not fully understood. The T-cell factor/Lymphoid enhancer factor (TCF/Lef;
hereafter TCF) transcription factors bind Wnt-responsive DNA elements (WREs) to control Wnt/β-catenin
target gene expression. Of the four TCF family members (TCF7, LEF1, TCF7L1, and TCF7L2) very little is
known about TCF7L1 in CRC and the set of target genes it directly regulates. By using shRNAs to deplete
TCF7L1 in established human CRC lines, we found that it promotes cell growth. Although microarray analysis
of transcripts differentially expressed in TCF7L1 knockdown cells versus controls uncovered hundreds of
genes, surprisingly, we failed to identify a Wnt target gene signature among this list. Moreover, published
ChIP-Seq data indicates that a substantial fraction of TCF-bound DNA elements lack consensus TCF binding
motifs. These findings suggest that TCF7L1 may primarily function outside the canonical Wnt signaling
pathway to promote oncogenesis. Additional work is needed to identify the constellation of direct target genes
that TCF7L1 regulates and whether its DNA-binding function is required to promote CRC growth. In Aim 1, we
will identify the TCF7L1-transcriptome by conducting unbiased and genome-wide functional genomics
approaches in control and TCF7L1-depleted CRC cells. In TCF7L1-depleted lines, we will introduce wild-type
and DNA-binding deficient TCF7L1 cDNAs to classify targets whose expression is regulated independently of
direct TCF7L1 binding to DNA. In Aim 2, we will determine whether the DNA-binding capacity of TCF7L1 is
required for CRC cell proliferation, progression through the cell cycle, growth in an anchorage-independent
manner, and tumorigenesis in vivo. We will also assess whether non-canonical targets are differentially
expressed in primary human colonic tissues and tumors. The vast majority of existing therapeutics designed to
target the Wnt pathway have focused on nuclear TCF/β-catenin complexes as the key regulator of the CRC
transcriptome. Our findings will establish TCF7L1 as a critical regulator of genes outside the canonical Wnt/β-
catenin pathway and will open a whole new field of research to exploit those targets for therapeutic
intervention.

## Key facts

- **NIH application ID:** 10040673
- **Project number:** 1R03CA244133-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Gregory S. Yochum
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $158,320
- **Award type:** 1
- **Project period:** 2020-07-10 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040673

## Citation

> US National Institutes of Health, RePORTER application 10040673, Dissecting the role of TCF7L1 in colorectal cancer (1R03CA244133-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10040673. Licensed CC0.

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