# Mechanisms of DNA methylation signaling and dysregulation in colon cancer

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $632,319

## Abstract

PROJECT SUMMARY
Colon cancer is a leading cause of cancer-related death for both men and women in the United States. Abnormal
DNA methylation patterning is an epigenetic hallmark of colon and other cancer types and is a major contributing
factor to genome instability and tumor suppressor gene silencing in this disease. Despite a deep appreciation of
roles for DNA methylation in development and cancer, causal mechanisms that contribute to the evolution of
DNA methylation abnormalities in colon and other cancer types, and consequences of this hallmark epigenetic
remodeling on cancer development, remain poorly understood. This proposal seeks to address these
fundamental knowledge gaps. Our preliminary data implicate protein ubiquitination as an essential post-
translational modification (PTM) regulating the activity of DNMT1, the primary enzyme responsible for the
epigenetic inheritance of DNA methylation patterns through mitotic cell divisions and a major target for epigenetic
cancer therapy. Building from these data, studies in Aim 1 will characterize the ubiquitin signaling network that
interfaces with DNA methylation inheritance. The therapeutic potential of targeting ubiquitin signaling regulators
in this pathway will also be considered. In Aim 2, we will test a mechanistic hypothesis connecting overexpression
of the E3 ubiquitin ligase UHRF1 to DNA methylation dysregulation and colon tumorigenesis. Aim 3 will
investigate a non-canonical function for UHRF1 in the regulation of heterochromatic histone PTM signaling and
its implications for DNA hypomethylation therapy. Overall, our studies at the interface of ubiquitin signaling and
DNA methylation inheritance will reveal fundamental causes and consequences of abnormal DNA methylation
signaling in colon cancer and identify novel approaches to enhance the efficacy of DNA hypomethylation therapy
as a treatment strategy to manage this deadly disease.

## Key facts

- **NIH application ID:** 10979595
- **Project number:** 1R01CA283463-01A1
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Scott Rothbart
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $632,319
- **Award type:** 1
- **Project period:** 2024-07-02 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979595

## Citation

> US National Institutes of Health, RePORTER application 10979595, Mechanisms of DNA methylation signaling and dysregulation in colon cancer (1R01CA283463-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10979595. Licensed CC0.

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