# Integrin alpha6beta4 regulation of cancer epigenetics

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $466,053

## Abstract

How DNA demethylation machinery can be targeted to specific genomic loci is still poorly understood, yet
has important implications for tumor biology. Mounting evidence suggests that the microenvironment
influences epigenetics; however, the mechanisms guiding these events have not been elucidated. We have
demonstrated that integrin α6β4 dramatically alters the transcriptome toward an invasive phenotype. The
integrin regulates this process, in part, by substantially changing the epigenome through the regulation of DNA
demethylation of select CpG rich regions and loci. Thus, we expect that understanding how integrin α6β4
regulates the cancer epigenome holds the key to how site-specific and mechanotransduced epigenetics are
regulated. Investigations into how integrin α6β4 regulates DNA demethylation (funded by an NCI R21) led to
our discovery that integrin α6β4 utilizes and stimulates the base excision repair (BER) pathway to mediate
these epigenetic events, but not in cells in which the link between integrin α6β4 and the nucleus is
compromised. We have also identified specific mutations in integrin β4 subunit that preventing the integrin from
binding to intermediate filaments and anchoring under the nucleus, thus indicating a pathway for integrin-
mediated alterations in nuclear function. Based on our preliminary data and supporting literature, we
hypothesize that integrin α6β4 coordinates signal and mechano-transduction to the nucleus that drives BER
and results in DNA demethylation of select loci, which in turn enhances tumor invasion and metastasis. We will
test our central hypothesis through completion of the following three aims: 1) Determine how integrin α6β4
cytoskeletal linkages impacts invasion, metastasis and epigenetics, 2) Elucidate how integrin α6β4 regulates
BER-mediated DNA demethylation, and 3) Define changes in the epigenome mediated by integrin α6β4
signaling. We expect that by elucidating the genes and pathways used by integrin α6β4 to modulate the
demethylation of select genes, we will provide critical insight into how specific sites within the genome are
demethylated to foster an invasive and metastatic transcriptome.

## Key facts

- **NIH application ID:** 9843117
- **Project number:** 5R01CA223164-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** KATHLEEN L. O'CONNOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $466,053
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843117

## Citation

> US National Institutes of Health, RePORTER application 9843117, Integrin alpha6beta4 regulation of cancer epigenetics (5R01CA223164-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9843117. Licensed CC0.

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