# Role of the Histone Modifier KDM2A in Lung Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $366,000

## Abstract

PROJECT SUMMARY
Lung cancer is the leading cause of cancer death in the US and worldwide. Non-small cell lung cancer
(NSCLC) accounts for as much as 85% of all lung cancer cases. The five year survival rate (16%) of NSCLC
patients is among the lowest in all malignancies and has not been significantly improved over the past three
decades. Histone lysine (K) methylation is considered a hallmark of transcriptional and epigenetic regulation of
gene expression. This modification is dynamically controlled by histone methylation modifiers, i.e., histone
lysine methyltransferases (methylation writers) and demethylases (methylation erasers). In contrast to great
advances in our understanding of kinase signaling pathways, the pathogenic roles of histone methylation
modifiers in NSCLC are largely unknown. In our search to identify histone methylation modifiers with
oncogenic function for NSCLC, we recently found that in NSCLC tumors, the histone H3 lysine 36 (H3K36)
demethylase KDM2A (also known as FBXL11 and JHDM1A) is frequently overexpressed. Our results showed
that KDM2A knockdown strongly inhibited tumorigenic and metastatic abilities of KDM2A-high NSCLC cells in
mouse xenograft models and that overexpression of KDM2A promoted the proliferation and invasion of
KDM2A-low NSCLC cells. The long-term goal is to define the role of the histone modifier KDM2A in lung
tumorigenicity. Our additional results revealed that KDM2A repressed tumor-suppressive genes, such as the
dual-specificity phosphatase 3 (DUSP3). They also indicate that KDM2A enhances ERK1/2 signaling important
for cell proliferation and invasion by epigenetically down-regulating the ERK1/2 phosphatase DUSP3. High
KDM2A levels were correlated with poor prognosis in two distinct NSCLC patient cohorts, indicating that
KDM2A is a novel poor prognostic epigenetic marker. Based on these definitive findings, our central
hypothesis is that KDM2A promotes NSCLC by epigenetically repressing tumor suppressor genes via
cooperation with KDM2A-associated protein (s). In the proposed study, we seek to understand the role of
KDM2A in lung tumorigenicity using molecular mechanistic studies, genome-wide chromatin sequencing
approaches, and our new genetic mouse models. Genetically engineered mouse models proposed here would
provide in vivo insights into how KDM2A promotes NSCLC. In addition, our studies promise to uncover new
cancer-epigenetic mechanisms by which KDM2A promotes lung cancer and will offer a rationale for the
development of a KDM2A-targeted therapy as a new epigenetic therapeutic approach for the treatment of a
substantial subset of NSCLC patients.

## Key facts

- **NIH application ID:** 10220879
- **Project number:** 5R01CA207098-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Min Gyu Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220879

## Citation

> US National Institutes of Health, RePORTER application 10220879, Role of the Histone Modifier KDM2A in Lung Cancer (5R01CA207098-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220879. Licensed CC0.

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