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 3

KDM2A’s catalytic activity is indispensable for in vitro proliferation and invasiveness of NSCLC cells, and stable KDM2A overexpression promotes cell proliferation, anchorage-independent growth, and cellular invasiveness.

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KDM2A’s catalytic activity is indispensable for in vitro proliferation a...
(A and B) Effect of ectopic expression of GFP, wild-type KDM2A, and its catalytic mutant mKDM2A (H212A) on the proliferation of KDM2A knockdown cells. Only wild-type KDM2A rescued defective proliferation of KDM2A-depleted H1792 and H1975 cells. The siControl-treated cells were used as controls. (C–F) Effect of ectopic expression of GFP, wild-type KDM2A, and its catalytic mutant mKDM2A (H212A) on the defective invasiveness of KDM2A-depleted H1792 (C and D) and H1975 (E and F) cells. Cells were treated with siKDM2A-3 to deplete KDM2A. Stained cells were quantified in at least 5 different fields (D and F). (G–L) Stable overexpression of KDM2A in H460 NSCLC cells containing low endogenous KDM2A levels. Two KDM2A-overexpressing H460 clones (KDM2A-1 and KDM2A-2) were generated using a retroviral system (G). Empty vector–infected cells (vector-cont) were used as control. Cell proliferation was examined by MTT assays (H). For colony formation assays, representative phase contrast image of colonies in soft agars are shown (I), and colony numbers were quantified (J). For in vitro cellular invasion assays, representative images of invaded cells are shown (K), and stained cells were quantified in at least 5 different fields (L). Scale bars: 200 μm (C, E, and K); 400 μm (I). *P < 0.05; **P < 0.01; ***P < 0.001.