Abstract 5146: The histone demethylase KDM2A is a new promoter of tumorigenesis, drug target and negative prognostic biomarker for non-small cell lung cancer

Abstract

Abstract The molecular etiology of non-small cell lung cancer (NSCLC) is heterogeneous and mostly dominated by alterations in kinase signaling pathways (i.e. KRAS, EGFR, EML4-ALK, PI3K, MEK1). Epigenetic modifiers, including histone methyltransferase and demethylases, have emerged as important regulators of oncogenic phenotypes in a small but growing number of tumor types, but the pathogenic role of histone methylation modifiers in NSCLC is largely unknown. We found that the histone H3 lysine 36 (H3K36) demethylase KDM2A is a novel oncogenic promoter of NSCLC. In our analysis KDM2A is frequently overexpressed in NSCLC cell lines and patient samples (≥14% in NSCLC tumors), and high expression levels of KDM2A correlate with poor prognosis in three independent patient populations from the USA and Asia. KDM2A knockdown by RNAi in KDM2A overexpressing cell lines inhibits proliferation and invasiveness of NSCLC cells in vitro and in three mouse xenograft models (subcutaneous, intravenous, and orthotopic models). Consistently, KDM2A overexpression promotes these cellular characteristics in NSCLC cell lines with low endogenous KDM2A levels. Rescue experiments using KDM2A-depleted cells showed that ectopic expression of wild-type KDM2A, but not its catalytic mutant mKDM2A, restored proliferation and invasion. These results indicate that the effect of KDM2A on oncogenic phenotypes is largely dependent on its catalytic activity and validate it as drug target for development of small molecule inhibitors. Mechanistically, we uncovered, that KDM2A activates the MAPK signaling pathway (ERK1/2) by transcriptionally repressing the MAPK phosphatase DUSP3. In summary, these novel findings indicate that KDM2A overexpression promotes NSCLC tumor growth and invasion. Our results provide new insights into how the dysregulation of an epigenetic enzyme can be coupled to activation of the ERK1/2 signaling pathway to promote NSCLC tumorigenesis and suggest that KDM2A is a promising anti-cancer therapeutic drug target for KDM2A-overexpressing NSCLC patients. Citation Format: Klaus W. Wagner, Hunain Alam, Shilpa S. Dhar, Uma Giri, Na Li, Yongkun Wei, Tina Cascone, Dipak Giri, Jae-Hwan Kim, Yuanqing Ye, Asha Multani, Chia-Hsin Chan, Baruch Erez, Babita Saigal, Hui-Kuan Lin, Xifeng Wu, Mien-Chie Hung, John Heymach, MinGyu Lee. The histone demethylase KDM2A is a new promoter of tumorigenesis, drug target and negative prognostic biomarker for non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5146. doi:10.1158/1538-7445.AM2014-5146