Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1.
Lysine demethylase 2A promotes stemness and angiogenesis of breast cancer by upregulating Jagged1.
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赖氨酸脱甲基酶2a通过上调锯齿状1促进乳腺癌的干性和血管生成1。
DOI：
10.18632/oncotarget.8381
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发表时间：
2016-05-10
期刊：
影响因子：
--
通讯作者：
Hung WC
中科院分区：
文献类型：
--
作者：
Chen JY;Li CF;Chu PY;Lai YS;Chen CH;Jiang SS;Hou MF;Hung WC
由甲基转移酶和去甲基酶动态调节的组蛋白甲基化的改变经常在人类癌症中发现。在此，我们发现赖氨酸脱甲基酶2A(KDM2A)在人类乳腺癌中的表达显著增加，其过度表达与肿瘤的进展和预后不良有关。乳腺癌细胞中KDM2a基因的敲除降低了细胞的增殖能力，但并没有降低细胞的存活率。基因集浓缩分析表明，抑制KDM2A可下调血管生成基因的表达，同时下调Notch信号通路中Jagged1(JAG1)、NOTCH1和HEY1的表达。染色质免疫沉淀-定量聚合酶链式反应(ChIP-qPCR)结果表明，在KDM2A缺失的MDA-MB-231细胞中，KDM2A与JAG1启动子结合，组蛋白H3(H3K36)的Lys-36甲基化增加。在KDM2A缺失的细胞中，肿瘤球的形成显着减少，这可以通过JAG1的异位表达而逆转。选择性KDM2a抑制剂达米肼也能减少肿瘤球数和CD24CD44Hi/−细胞数。此外，达米肼与顺铂在细胞杀伤中具有协同作用。我们发现SOX2是KDM2A促进肿瘤干细胞分化的直接转录靶点。去除MDA-MB-231细胞中的KDM2A可减少共培养的内皮细胞中缺口的激活和管状的形成。两个促血管生成因子JAG1和PDGFA是KDM2A促进血管生成的关键介质。最后，在原位动物实验中，抑制KDM2A显著减少了肿瘤生长和血管生成。综上所述，我们得出结论，KDM2A通过上调JAG1来促进干性、化疗耐药性和血管生成，从而在乳腺癌中发挥癌基因的作用。
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.
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影响因子：
--
作者：
England KS;Tumber A;Krojer T;Scozzafava G;Ng SS;Daniel M;Szykowska A;Che K;von Delft F;Burgess-Brown NA;Kawamura A;Schofield CJ;Brennan PE
通讯作者：
Brennan PE
DOI：
10.1073/pnas.0709663105
发表时间：
2008-02-12
影响因子：
11.1
作者：
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通讯作者：
Epstein, Jonathan A.
影响因子：
64.8
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
12.4
作者：
Kim, S-H;Kim, E-J;Kim, H.
通讯作者：
Kim, H.