# Delineating the Role of KAP1 in WNT-induced Colorectal Cancer

> **NIH NIH R03** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $82,000

## Abstract

PROJECT SUMMARY
 Cell signaling - transcriptional programs play diverse roles in normal development including the regulation of
metabolism, cell survival/death, and differentiation, all of which can malfunction in tumorigenesis. The WNT
program maintains cell stemness and is highly proliferative, properties that cancer cells hijack to initiate and
sustain tumorigenesis. A large body of work has defined that the WNT program is important for both CRC
initiation and progression. However, despite previous molecular characterization and identification of small
molecules that target the WNT program at multiple levels, a therapeutic arm that successfully inactivates WNT
has yet to be employed. Our studies have defined that the transcriptional coregulator KAP1/TRIM28 is required
for expression of WNT target genes upon oncogenic WNT activation, suggesting that KAP1 is an alternative
drug target in WNT-induced CRC. As such, targeting KAP1 in CRC will require comprehensive characterization
of druggable pockets, that if perturbed, would prevent KAP1-dependent oncogenic WNT activation and
downstream hallmarks of cancer. Our published studies have identified a mechanism whereby KAP1 uses a
previously uncharacterized chromatin reader cassette to directly bind hypoacetylated Histone 4 tails surrounding
promoters of non-WNT genes (to facilitate their activation). Our unpublished studies have provided evidence of
KAP1 interaction with the pathway- and sequence-specific factor β-Catenin. However, it remains unknown if the
chromatin- and β-Catenin–binding activities are critical for KAP1 recruitment to, and for activation of, WNT target
genes to support WNT-dependent hallmarks of cancer.
 Given these findings and critical gaps in knowledge, the central hypothesis of this proposal is that KAP1
uses its chromatin- and β-Catenin–binding functions to activate the oncogenic WNT program to promote CRC
transformation and proliferation. As such, the major goal of this research proposal is to explore if KAP1 utilizes
these functions to activate WNT target genes, and whether their perturbation would block WNT target gene
activation and WNT-induced CRC phenotypes (CRC transformation and cell proliferation). To accomplish this
goal, we will leverage the power of genomics (integrated RNA-seq/ChIP-seq approach) and phenotypic assays
in established models of CRC tumorigenesis (normal and oncogenic colon epithelial cells). Specifically, we will
explore if KAP1 binds WNT target loci upon oncogenic WNT activation in normal colon epithelial cells and
whether KAP1 chromatin- and β-Catenin–binding capabilities are required to activate WNT target genes (Aim
1) and to sustain hallmarks of cancer (Aim 2). The basic science research proposed in this “self-contained
proposal” will not only reveal fundamental principles of how chromatin readers operate in the context of cancer
but also pave the way to identify KAP1 targeting approaches, which is in-line with NCI’s mission to identify novel
th...

## Key facts

- **NIH application ID:** 10358964
- **Project number:** 1R03CA259672-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ivan D'Orso
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $82,000
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358964

## Citation

> US National Institutes of Health, RePORTER application 10358964, Delineating the Role of KAP1 in WNT-induced Colorectal Cancer (1R03CA259672-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10358964. Licensed CC0.

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