KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling
Klaus W. Wagner, … , John V. Heymach, Min Gyu Lee
Klaus W. Wagner, … , John V. Heymach, Min Gyu Lee
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5231-5246. https://doi.org/10.1172/JCI68642.
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Research Article Oncology

KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling

Abstract

Epigenetic dysregulation has emerged as a major contributor to tumorigenesis. Histone methylation is a well-established mechanism of epigenetic regulation that is dynamically modulated by histone methyltransferases and demethylases. The pathogenic role of histone methylation modifiers in non–small cell lung cancer (NSCLC), which is the leading cause of cancer deaths worldwide, remains largely unknown. Here, we found that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is frequently overexpressed in NSCLC tumors and cell lines. KDM2A and its catalytic activity were required for in vitro proliferation and invasion of KDM2A-overexpressing NSCLC cells. KDM2A overexpression in NSCLC cells with low KDM2A levels increased cell proliferation and invasiveness. KDM2A knockdown abrogated tumor growth and invasive abilities of NSCLC cells in mouse xenograft models. We identified dual-specificity phosphatase 3 (DUSP3) as a key KDM2A target gene and found that DUSP3 dephosphorylates ERK1/2 in NSCLC cells. KDM2A activated ERK1/2 through epigenetic repression of DUSP3 expression via demethylation of dimethylated H3K36 at the DUSP3 locus. High KDM2A levels correlated with poor prognosis in NSCLC patients. These findings uncover an unexpected role for a histone methylation modifier in activating ERK1/2 in lung tumorigenesis and metastasis, suggesting that KDM2A may be a promising therapeutic target in NSCLC.

Authors

Klaus W. Wagner, Hunain Alam, Shilpa S. Dhar, Uma Giri, Na Li, Yongkun Wei, Dipak Giri, Tina Cascone, Jae-Hwan Kim, Yuanqing Ye, Asha S. Multani, Chia-Hsin Chan, Baruch Erez, Babita Saigal, Jimyung Chung, Hui-Kuan Lin, Xifeng Wu, Mien-Chie Hung, John V. Heymach, Min Gyu Lee

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Figure 1

KDM2A levels are frequently increased in NSCLC cell lines and tumors, and the KDM2A gene appears to undergo amplification in KDM2A-overexpressing NSCLC cell lines.

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KDM2A levels are frequently increased in NSCLC cell lines and tumors, an...
(A and B) Expression levels of histone demethylases (A) and methyltransferases (B) in 54 NSCLC cell lines. The KDM2A mRNA levels were determined by Affymetrix U133P microarray analysis (the probe set: 208988_at). (C) Comparison of KDM2A mRNA levels in 2 normal epithelial cell lines and 54 NSCLC cell lines. KDM2A mRNA levels were from Affymetrix U133P microarray data. (D) Analysis of KDM2A mRNA levels in 103 NSCLC tumors (stages I–III) and 40 adjacent normal lung tissue samples from UT MD Anderson Cancer Center by quantitative RT-PCR. The cut-off value (red line) is 500, which represents the highest normal value among 40 normal lung tissues. The lowest PCR value of KDM2A mRNA levels examined was set at 1. (E) Representative photographs from IHC analysis of KDM2A protein levels in normal and tumor samples (related to Table 1). Scale bars: 50 μm. (F and G) Analysis of relative KDM2A mRNA and protein levels in 3 KDM2A-overexpressing NSCLC cell lines (H1792, H1975, and H23) and 2 NSCLC cell lines containing low KDM2A levels (H460 and H2122) by quantitative RT-PCR (F) and Western blot (G), respectively. β-Actin was used as an internal loading control. (H) Amplification of KDM2A and cyclin D1 genes. Copy numbers of KDM2A and cyclin D1 were quantified by DNA PCR.