# Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $122,508

## Abstract

PROJECT SUMMARY
Epimutation – mitotically stable gene silencing associated with epigenetic alteration in DNA methylation – is
now recognized as a common feature of human cancer. Indeed, recent epigenomic studies revealed that
nearly all tumor types harbor hundreds of aberrantly hypermethylated and silenced promoter CpG island-
associated (CGI-associated) genes, highlighting the need to identify driver epimutations. In this regard, we
developed a novel mouse model of epimutation in a tumor suppressor gene p16 (also known as cyclin-
dependent kinase inhibitor 2A). We found that engineered promoter methylation leads to accelerated p16
epimutation in mouse somatic tissues during aging. We demonstrated that p16 epimutation predisposes mice
to spontaneous tumor development. In addition, our preliminary work shown that p16 epimutation can
cooperate with mutational Apc to accelerate intestinal tumorigenesis using the ApcMin/+ mice. Importantly, we
found that p16 epimutation functions beyond the classically known cell-cycle control to induce malignant
transformation of intestinal neoplasms. Therefore, based on our strong preliminary data, we hypothesize that
p16 epimutation, commonly observed in human sporadic CRCs as part of the age-related epigenetic alteration,
cooperates with genetic alterations to drive intestinal cancer initiation and progression. We will test this by 1)
Determine how p16 epimutation promotes intestinal tumorigenesis. We will assess the biological
consequences of p16 epimutation through its interactions with two key signaling pathways: WNT-APC-β-
catenin and MAPK-RAS-RAF; 2) Determine whether reversal of epigenetic defects in p16 suppresses tumor
growth. We will evaluate tumor responses to the reversal of p16 epimutation by applying a CRISPR-based
targeted p16 promoter demethylation; and 3) Determine whether transcription factors as a reader of
methylated DNA mediate the function of p16 epimutation. We will investigate the molecular events by which
p16 epigenetic silencing is a result from DNA methylation dependent trans-acting protein binding which
subsequently recruits chromatin repressive complexes. These studies will elucidate how aberrant DNA
methylation, an important epigenetic mechanism regulating the expression of tumor suppressor genes, drives
colorectal tumorigenesis. The results derived from this proposal could have a unique impact in the design of
colon cancer epigenetic therapies.

## Key facts

- **NIH application ID:** 10129033
- **Project number:** 3R01CA233472-02S1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lanlan Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $122,508
- **Award type:** 3
- **Project period:** 2019-08-08 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129033

## Citation

> US National Institutes of Health, RePORTER application 10129033, Defining the Function of Age-Related Epimutation in Intestinal Tumorigenesis (3R01CA233472-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129033. Licensed CC0.

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