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 7

KDM2A is essential for tumor growth and metastasis of NSCLC cells in vivo.

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KDM2A is essential for tumor growth and metastasis of NSCLC cells in viv...
(A and B) Effect of KDM2A knockdown on lung tumor colonization in an intravenous mouse xenograft model. H1792 cells treated with siControl RNA or 2 siRNAs against KDM2A were injected into mouse tail veins, and lung tumor formation was monitored. Representative gross images of lung show a lung-metastasized tumor (white arrow) in a control siRNA group mouse as compared with a tumor-free lung from a siKDM2A-3 group mouse (A). H&E-stained microscopic images display lung-metastasized tumor (adenocarcinoma) in a control siRNA group mouse in contrast with tumor-free normal lung histology in siKDM2A group mice (B). (C and D) Effect of KDM2A knockdown on formation of metastatic lesions in an orthotopic lung mouse xenograft model. H1792 cells treated with siControl or siKDM2A-3 were implanted into the parenchyma of left lung, and the contralateral lungs and lymph nodes were monitored for metastasis. Representative gross images of lung show massive multiple tumors (arrows) in a control siRNA group mouse as compared with a tiny tumor in a siKDM2A group mouse (C). H&E-stained microscopic images display massive tumors in control siRNA group mice in contrast with none or a miniscule tumor in siKDM2A group mice (D). Scale bars: 200 μm.