Abstract
Alterations of histone methylation dynamically regulated by methyltransferases and demethylases are frequently found in human cancers. Here, we showed that expression of lysine demethylase 2A (KDM2A) is markedly increased in human breast cancer and its overexpression is associated with tumor progression and poor prognosis. Knockdown of KDM2A in breast cancer cells reduced proliferation but not viability. Gene set enrichment analysis revealed that inhibition of KDM2A down-regulates angiogenic genes with concurrent reduction of Jagged1 (JAG1), NOTCH1 and HEY1 in the NOTCH signaling. Chromatin immunoprecipitation- quantitative polymerase chain reaction (ChIP-qPCR) demonstrated the binding of KDM2A to the JAG1 promoter and the increase of methylation of Lys-36 of histone H3 (H3K36) in KDM2A-depleted MDA-MB-231 cells. Tumorsphere formation was significantly reduced in KDM2A-depleted cells which could be reversed by ectopic expression of JAG1. A selective KDM2A inhibitor daminozide also decreased the number of tumorsphere and the number of CD24−/CD44hi cells. In addition, daminozide acted synergistically with cisplatin in cell killing. We identified SOX2 as a direct transcriptional target of KDM2A to promote cancer stemness. Depletion of KDM2A in MDA-MB-231 cells attenuated NOTCH activation and tube formation in co-cultured endothelial cells. Two pro-angiogenic factors JAG1 and PDGFA are key mediators for KDM2A to enhance angiogenesis. Finally, inhibition of KDM2A significantly decreased tumor growth and angiogenesis in orthotopic animal experiments. Collectively, we conclude that KDM2A functions as an oncogene in breast cancer by upregulating JAG1 to promote stemness, chemoresistance and angiogenesis.
Highlights
Histone proteins are the building components of the nucleosome, the basic unit of DNA packaging in eukaryotic cells
Because JAG1 is the ligand for NOTCH1, we investigated whether KDM2A depletion reduces JAG1 expression and found that it is the case (Figure 3B)
Our results suggested that KDM2A upregulates JAG1 to promote NOTCH activation which directly activates the transcription of SOX2 gene in breast cancer cells
Summary
Histone proteins are the building components of the nucleosome, the basic unit of DNA packaging in eukaryotic cells. Histone proteins undergo different post-translational modifications (PTMs) including phosphorylation, acetylation, methylation, sumoylation and ubiquitination. These modifications affect the compact of chromatin structure and the interactions between non-histone proteins and chromatin to modulate gene expression. Tri-methylation of lysine 4 of histone H3 (H3K4) is strongly associated with transcriptional activation and is frequently found around the transacription start sites of www.impactjournals.com/oncotarget highly expressed genes, whereas H3K27 tri-methylation is usually linked with transcriptional inhibition and is detected in the promoters of silenced genes [4,5,6]. In contrast to the repressive role of H3K27 tri-methylation, recent study suggested that mono-methylated H3K27 accumulates within active genes and promotes transcriptional activation [7]
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