Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo.
Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo.
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DOI：
10.1038/onc.2012.352
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发表时间：
2013-07-11
期刊：
影响因子：
8
通讯作者：
Mandal, S. S.
中科院分区：
文献类型：
--
作者：
Ansari, K. I.;Kasiri, S.;Mandal, S. S.
混合谱系白血病（MLL）是人类组蛋白H3赖氨酸-4特异性甲基转移酶，在基因表达、表观遗传学和癌症中起关键作用。在此，我们证明了反义介导的MLL1敲低可诱导培养细胞的细胞周期阻滞和凋亡。有趣的是，应用MLL1反义蛋白特异性地在体内敲除MLL1，并抑制裸鼠移植子宫颈肿瘤的生长。mll1敲低可下调肿瘤组织中影响肿瘤生长的各种生长和血管生成因子，如HIF1α、VEGF和CD31。MLL1沿血管网线过表达，定位于表达CD31的内皮细胞层附近，提示MLL1在血管发生中的潜在作用。MLL1也与HIF1α一起在缺氧区过表达。总的来说，我们的研究表明，MLL1在缺氧信号、血管发生和肿瘤生长中起着关键作用，它的缺失抑制了体内肿瘤的生长，这表明它在新型癌症治疗中具有潜力。
Mixed lineage leukemias (MLL) are human histone H3 lysine-4 specific methyl transferases that play critical roles in gene expression, epigenetics, and cancer. Herein, we demonstrated that antisense-mediated knockdown of MLL1 induced cell cycle arrest and apoptosis in cultured cells. Intriguingly, application of MLL1-antisense specifically knocked down MLL1 in vivo and suppressed the growth of xenografted cervical tumor implanted in nude mouse. MLL1-knockdown downregulated various growth and angiogenic factors such as HIF1α, VEGF and CD31 in tumor tissue affecting tumor growth. MLL1 is overexpressed along the line of vascular network and localized adjacent to endothelial cell layer expressing CD31, indicating potential roles of MLL1 in vasculogenesis. MLL1 is also overexpressed in the hypoxic regions along with HIF1α. Overall, our studies demonstrated that MLL1 is a key player in hypoxia signaling, vasculogenesis, and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy.
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