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 8

Stable knockdown of KDM2A drastically inhibits tumor growth of NSCLC cells in vivo, and high KDM2A correlates with poor prognosis of lung cancer patients.

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Stable knockdown of KDM2A drastically inhibits tumor growth of NSCLC cel...
(A–E) The effect of stable knockdown of KDM2A on tumor growth ability of NSCLC cells in a subcutaneous mouse xenograft model. Stably KDM2A-depleted H1792 cells were generated using shK–DM2A#1- and shKDM2A#2–containing viruses. KDM2A, DUSP3, and phospho-ERK1/2 levels were determined by Western blot analysis (A). Cell proliferation was measured by MTT assays (B). Stable KDM2A knockdown (shKDM2A#1 and shKDM2A#2) cells and control cells (shLuciferase) were subcutaneously injected into mice (n = 5 for each group). Tumor development was monitored and plotted for 11 weeks (C). Representative pictures of tumors developed in nude mice are shown, and tumors are indicated by black arrows in dotted circles (D). Representative images of IHC staining (anti-KDM2A, anti-DUSP3, and anti–phospho-ERK1/2) and H&E staining of tumor tissues are shown (E). Scale bars: 50 μm. (F) Kaplan-Meier survival rate analysis of the tumor set from UT MD Anderson Cancer Center. Tumor samples with patient history (n = 98 out of 103 samples; see Figure 1D) were classified as high KDM2A or low KDM2A by a cut-off value of 500. (G) Survival rate analysis of an NSCLC patient set on the basis of KDM2A protein levels measured by IHC (n = 76). From tumor samples in Table 1, KDM2A high (n = 38) and KDM2A low (n = 38) with patient history were used for this analysis.