# DNA hypermethylation in lung tumors

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2022 · $467,261

## Abstract

PROJECT SUMMARY:
Epigenetic dysregulation is now widely recognized as a prominent feature of cancer cells. However,
mutations in epigenetic modifier genes such as DNA and histone methyltransferases or 5-methylcytosine
(5mC) oxidases can explain only a limited fraction of misregulated epigenomes in cancer. A pervasive
feature of cancer epigenomes is CpG island DNA hypermethylation. Despite the fact that these methylation
events have been cataloged in thousands of publications and in some instances, have been used to
classify tumors, we still do not understand the mechanisms how these DNA methylation changes arise. In
several types of tumors, a large percentage of the cancer-associated DNA hypermethylation events at
CpG islands occur at Polycomb-marked genes. Therefore, one can view the occupancy of CpG islands by
Polycomb complexes as one mechanism that protects them from de novo DNA methylation. However, this
is likely not the only methylation-protective mechanism that operates at CpG islands. Mammalian genomes
encode a relatively small set of 12 proteins that contain a CXXC-type zinc finger domain known to tightly
bind to unmethylated CpG-rich DNA sequences. All of these proteins are known or suspected chromatin
modifiers. The family includes the 5mC oxidases (the TET proteins), as well as histone lysine
methyltransferases and demethylases. We propose that the common function of the majority of the CXXC
proteins is to protect CpG islands from DNA methylation. Furthermore, metabolic disturbances of the TCA
cycle can affect the function of multiple a-ketoglutarate-dependent dioxygenase enzymes. Remarkably, 5
of the 12 CXXC proteins belong to this class of enzymes. We hypothesize that there is functional
redundancy in multiple mechanisms that protect CpG islands from DNA methylation. Overall, our main
hypothesis is that a breakdown of multiple CpG island protection mechanisms, including downregulation
of Polycomb components and dysfunction of CXXC proteins will lead to CpG island hypermethylation in
cancer. We propose to identify these protective factors by a systematic approach using gene inactivation
of Polycomb components and of CXXC proteins and comprehensive chromatin mapping studies combined
with genome-wide DNA methylation assays after manipulating the different CpG island binding factors.
The study will use human bronchial cells and will focus on lung cancer for which we have previously
established comprehensive lists of tumor-methylated CpG islands. We consider that a combined deficiency
of Polycomb components and of CXXC protein function will explain the common hypermethylation of
Polycomb target genes observed in tumors. The role of accumulation of TCA cycle metabolites that inhibit
dioxygenases and loss of Polycomb proteins will be tested to determine if DNA methylation can be targeted
in this way to resemble a prevalent cancer-like pattern. These studies will provide insights into the long-
sought mechanisms of DNA hypermethylation in ...

## Key facts

- **NIH application ID:** 10472533
- **Project number:** 5R01CA234595-04
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Gerd P Pfeifer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $467,261
- **Award type:** 5
- **Project period:** 2019-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472533

## Citation

> US National Institutes of Health, RePORTER application 10472533, DNA hypermethylation in lung tumors (5R01CA234595-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10472533. Licensed CC0.

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