Abstract 2192: Genomic amplification and drug-resistance roles of the KDM5A histone demethylase gene in breast cancer

Abstract

Interconnected genetic and epigenetic events control both the initiation and progression of cancer. Specifically, genetic alterations, such as amplification, and the subsequent over-expression of genes encoding ‘epigenetic modifying enzymes’ can directly lead to histone code changes that may be critical for cancer progression. KDM5A (lysine (K)-specific demethylase 5A, also known as RBP2 and JARID1A) was originally identified as the retinoblastoma-binding protein (RBP) implicated in the regulation of retinoblastoma target genes. Recently, several groups discovered that KDM5A is a member of a set of newly identified histone demethylases that control the chromatin-mediated regulation of gene expression. Specifically, KDM5A can function as a transcriptional repressor through the demethylation of tri- and dimethylated histone H3 at lysine 4 (H3K4) active marks. In this study, we observed a significant amplification and over-expression of the KDM5A gene in various tumors, including breast cancer. We found that breast cancer cells with KDM5A gene amplification had intrinsic drug resistance properties and knocking down KDM5A with shRNAs improved the efficacy of epidermal growth factor receptor (EGFR) inhibitors against these breast cancer cells. Further, up-regulation of KDM5A modified the histone methylation status and altered the expression of a subset of key genes, including the tumor suppressor p21 and the apoptotic effector BAK1, in breast cancer. Our findings suggest that alteration of the KDM5A gene may have a critical role in the pathogenesis of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2192. doi:1538-7445.AM2012-2192

Histone Demethylase RBP2 Is Critical for Breast Cancer Progression and Metastasis

“…For example, RBP2 amplification was reported in approximately 15% of breast cancers (Hou et al, 2012). We showed previously that RBP2 is critical for endocrine tumor formation in mice lacking Rb and menin tumor suppressors (Lin et al, 2011).…”

Identification of Small Molecule Inhibitors of Jumonji AT-rich Interactive Domain 1B (JARID1B) Histone Demethylase by a Sensitive High Throughput Screen

“…As the JARID1 enzymes contribute strongly to tumorigenesis and drug resistance in multiple cancer types (2,38), 4 these inhibitors may also be effective for cancer therapy in those settings.…”

Transformer2 proteins protect breast cancer cells from accumulating replication stress by ensuring productive splicing of checkpoint kinase 1

“…Other genes containing Tra2α/Tra2β target exons with G2 and S phase checkpoint that is essential in many cancer cells to prevent damaged chromosomes from entering mitosis [38] Vigilin (HDLBP) Represses proto-oncogene c-fms in breast cancer [43][44][45] KDM5A, KDM3A Histone methylases, erase epigenetic information, tumour promoters [46,47] NCOA Chromatin remodeling protein involved in breast cancer [48] ATRX Frequently mutated in paediatric cancer [49] SMC4 Key role in lung cancer, over-expressed in liver cancer [50,51] Nap1L1…”