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 4

DUSP3 is highly upregulated by KDM2A knockdown.

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DUSP3 is highly upregulated by KDM2A knockdown. (A) Venn diagrams and...
(A) Venn diagrams and a heat map of genes that are consistently 1.5-fold upregulated (top) or 2-fold downregulated (bottom) by KDM2A knockdown. The order of genes in the list does not necessarily reflect the importance of KDM2A-regulated genes because it is based simply on the mean of fold changes in expression that were induced by KDM2A knockdown. H1792 and H1975 cells were treated with siControl, siKDM2A-3, or siKDM2A-4 and harvested 48 hours later. The mRNA levels in KDM2A knockdown cells were measured by Affymetrix U133P and compared with those in siControl-treated cells. (B and C) Expression levels of KDM2A, DUSP3, GPR157, TMEM65, TIMM17, and GPR107 in H1792 (B) and H1975 (C) cells after KDM2A knockdown. The mRNA levels were analyzed by quantitative RT-PCR. (D) The effect of KDM2A knockdown on DUSP3 protein levels. DUSP3 and KDM2A levels were assessed by Western blot analysis using antibodies to DUSP3 in H1792 and H1975 cells. β-Actin was used as an internal loading control. (E and F) Analysis of DUSP3 mRNA levels in KDM2A-depleted H1792 (E) and H1975 (F) cells after ectopic expression of GFP, wild-type KDM2A, and its catalytic mutant mKDM2A (H212A). The DUSP3 mRNA levels were quantified by RT-PCR. (G and H) Analysis of TIMM17 mRNA levels in KDM2A-depleted H1792 (G) and H1975 (H) cells after ectopic expression of GFP, wild-type KDM2A, and its catalytic mutant mKDM2A (H212A). The TIMM17 mRNA levels were quantified by RT-PCR. *P < 0.05; **P < 0.01; ***P < 0.001.