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 5

KDM2A demethylates H3K36me2 at the proximal promoter and the 5′ end of the DUPS3 gene.

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KDM2A demethylates H3K36me2 at the proximal promoter and the 5′ end of t...
(A and B) Analysis of occupied levels of KDM2A at the DUSP3, GPR157, TMEM65, TIMM17, and GPR107 genes in H1792 (A) and H1975 (B) cells. Chromatin levels of KDM2A were measured by quantitative ChIP. (C) Diagrammatic representation of the distal promoter region (a), and the proximal promoter regions (b and c), and the 5′ end (d) of the DUSP3 gene. Arrows indicate the PCR-amplified regions. TSS, transcription start site. (D–I) Analysis of occupied levels of KDM2A (D and E), H3K36me2 (F and G), and H3 (H and I) at the DUSP3 gene in H1792 (D, F, and H) and H1975 (E, G, and I) cells. Chromatin levels of KDM2A, H3K36me2, and H3 were measured by quantitative ChIP. (J–M) Analysis of occupied levels of KDM2A, H3K36me2, H3K4me3, H3K27me3, and H3 at the promoter region in the DUSP3 gene (J and K) and at the GPR107 gene (L and M) in H1792 (J and L) and H1975 (K and M) cells. Chromatin levels of KDM2A, H3K36me2, H3K4me3, H3K27me3, and H3 were measured by quantitative ChIP. For direct comparison, KDM2A levels of the region c in D and E are replotted in J and K. Anti-H3 was used as a ChIP control. *P < 0.05; **P < 0.01.