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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 12 Pg. 5231-46 (Dec 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 24200691 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• F-Box Proteins
• Histones
• Neoplasm Proteins
• RNA, Messenger
• RNA, Neoplasm
• Jumonji Domain-Containing Histone Demethylases
• KDM2A protein, human
• DUSP3 protein, human
• Dual Specificity Phosphatase 3

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (genetics, pathology)
• Cell Division
• Cell Line, Tumor
• Dual Specificity Phosphatase 3 (biosynthesis, genetics, physiology)
• Epigenesis, Genetic (genetics, physiology)
• F-Box Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Female
• Gene Expression Regulation, Neoplastic (genetics, physiology)
• Heterografts
• Histones (metabolism)
• Humans
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Lung Neoplasms (genetics, pathology)
• MAP Kinase Signaling System
• Male
• Methylation
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, physiology)
• Prognosis
• Promoter Regions, Genetic
• Protein Processing, Post-Translational (genetics, physiology)
• RNA Interference
• RNA, Messenger (biosynthesis, genetics)
• RNA, Neoplasm (biosynthesis, genetics)