# The Role of the Epigenetic Regulator UHRF1 in Colon Tumorigenesis

> **NIH NIH F32** · VAN ANDEL RESEARCH INSTITUTE · 2020 · $69,306

## Abstract

PROJECT SUMMARY
Alterations to the normal DNA methylation patterns that regulate all chromatin-templated processes is a hallmark
of cancer. Global DNA hypomethylation and local hypermethylation contribute to malignant transformation and
the silencing of tumor suppressor genes (TSGs). Specific patterns of DNA hypermethylation are particularly
present in a subclass of proximal colorectal cancers (CRC). These right-sided colorectal tumors often present
with the CpG Island Methylator Phenotype (CIMP) in which many normally unmethylated promoter CpG islands
are hypermethylated with high consistency and frequency. How these abnormal DNA methylation patterns are
established and propagated remains unclear, while therapeutic agents intended to reverse DNA
hypermethylation do not currently meet the needs of CRC patients. One protein with appealing attributes that
may explain how DNA hypermethylation occurs in CRC is the E3 ligase and epigenetic regulator UHRF1. UHRF1
directs DNA methylation through recruitment of the maintenance DNA methyltransferase DNMT1 to newly
replicated DNA. Evidence suggests UHRF1 is overexpressed and its function in DNA methylation is
misappropriated in many cancers, including CRC. The objective of this proposal is to define the subclass of
CRCs influenced by high UHRF1 levels and determine the mechanism through which UHRF1 contributes to
CRC by altering DNA methylation levels and patterns. Aim 1 will identify the subclass of CRC most associated
with high UHRF1 expression. This is critical to determining the CRC context for which inhibition of UHRF1 would
have therapeutic benefit. This Aim will use primary human colon tumor tissue to segregate UHRF1-high tumors
with epigenetic phenotypes. Aim 2 addresses the role of UHRF1 in colon tumor formation and maintenance. This
aim will utilize an ex vivo model system of intestinal organoids derived from mouse intestinal epithelia. This
system allows for precise control of the onset of an intestinal tumor phenotype to facilitate understanding of the
contribution of UHRF1 to either tumor initiation or maintenance and changes in DNA methylation during this
course. Finally, Aim 3 queries other gene targets identified to regulate the epigenetic-mediated silencing of
TSGs. These targets were determined through a genome-wide screen and include both known epigenetic
regulators and proteins previously unknown to regulate TSG silencing. As reversal of DNA hypermethylation is
necessary for reactivation of TSGs, a long-term goal of this project is to gain a better understanding of the
mechanisms necessary for reactivating TSGs that have been epigenetically silenced and using that information
to refine CRC treatments. Thus, this proposal will address in which genetic/epigenetic subclass and at what point
in tumor formation UHRF1 is important, in addition to better understanding TSG silencing through epigenetic
modifications. This has high relevance to public health given the prevalence of CRC and the cr...

## Key facts

- **NIH application ID:** 9960452
- **Project number:** 5F32CA225043-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Alison Ann Lanctot Chomiak
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2018-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960452

## Citation

> US National Institutes of Health, RePORTER application 9960452, The Role of the Epigenetic Regulator UHRF1 in Colon Tumorigenesis (5F32CA225043-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9960452. Licensed CC0.

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