Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
Oncogene. 2013 Jul 11;32(28):3359-70. doi: 10.1038/onc.2012.352. Epub 2012 Aug 27.
Mixed lineage leukemias (MLLs) are human histone H3 lysine-4-specific methyl transferases that have 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 factor in hypoxia signaling, vasculogenesis and tumor growth, and its depletion suppresses tumor growth in vivo, indicating its potential in novel cancer therapy.
混合谱系白血病（MLLs）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具有关键作用。在此，我们证明了反义介导的 MLL1 敲低可诱导培养细胞中的细胞周期停滞和细胞凋亡。有趣的是，MLL1 反义的应用特异性地在体内敲低了 MLL1，并抑制了植入裸鼠的异种移植宫颈癌的生长。MLL1 敲低下调了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 在沿血管网络的线上过表达，并定位于表达 CD31 的内皮细胞层附近，表明 MLL1 在血管生成中的潜在作用。MLL1 也与 HIF1α 一起在缺氧区域过表达。总的来说，我们的研究表明 MLL1 是缺氧信号、血管生成和肿瘤生长的关键因素，其耗竭抑制体内肿瘤生长，表明其在新型癌症治疗中的潜力。
