BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells.
BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells.
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DOI：
10.1038/srep38723
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发表时间：
2016-12-09
影响因子：
4.6
通讯作者：
Kaminska B
中科院分区：
文献类型：
--
作者：
Ciechomska IA;Przanowski P;Jackl J;Wojtas B;Kaminska B
胶质母细胞瘤(GBM)含有罕见的胶质瘤干细胞(GSCs)，具有自我更新、多向分化、对常规治疗耐药等特点。GSCs的药物诱导分化被认为是一种很有前途的抗胶质瘤治疗方法。越来越多的证据表明，干细胞的独特特性取决于自噬。在这里，我们证明了G9a组蛋白甲基转移酶的抑制剂BIX01294(引入了H3K9me2和H3K27me3抑制标记)在人胶质瘤细胞中触发自噬。药物或遗传抑制自噬减少了BIX01294处理细胞中LC3-II的积聚和GFP-LC3的点滴率。来源于胶质瘤细胞和GBM患者来源的GSCs富集球表达的自噬相关(ATG)基因水平低于亲代胶质瘤细胞培养物。典型的分化诱导剂在球体培养中上调神经元和星形细胞标志物，增加ATG mRNAs的水平。G9a与GSCs中自噬基因(LC3B、WIPI1)和分化相关基因(GFAP、TUBB3)的启动子结合。研究基因启动子的H3K4me3(激活标记)和H3K9me2(抑制标记)水平在血清分化细胞中高于球形培养细胞。BIX01294治疗上调GSCs自噬和分化相关基因的表达。药物抑制自噬可降低BIX01294诱导的GSCs中GFAP和TUBB3的表达，提示BIX01294诱导的GSCs分化依赖于自噬。
Glioblastoma (GBM) contains rare glioma stem-like cells (GSCs) with capacities of self-renewal, multi-lineage differentiation, and resistance to conventional therapy. Drug-induced differentiation of GSCs is recognized as a promising approach of anti-glioma therapy. Accumulating evidence suggests that unique properties of stem cells depend on autophagy. Here we demonstrate that BIX01294, an inhibitor of a G9a histone methyltransferase (introducing H3K9me2 and H3K27me3 repressive marks) triggers autophagy in human glioma cells. Pharmacological or genetic inhibition of autophagy decreased LC3-II accumulation and GFP-LC3 punctation in BIX01294-treated cells. GSCs-enriched spheres originating from glioma cells and GBM patient-derived cultures express lower levels of autophagy related (ATG) genes than the parental glioma cell cultures. Typical differentiation inducers that upregulate neuronal and astrocytic markers in sphere cultures, increase the level of ATG mRNAs. G9a binds to the promoters of autophagy (LC3B, WIPI1) and differentiation-related (GFAP, TUBB3) genes in GSCs. Higher H3K4me3 (an activation mark) and lower H3K9me2 (the repressive mark) levels at the promoters of studied genes were detected in serum-differentiated cells than in sphere cultures. BIX01294 treatment upregulates the expression of autophagy and differentiation-related genes in GSCs. Pharmacological inhibition of autophagy decreases GFAP and TUBB3 expression in BIX01294-treated GSCs suggesting that BIX01294-induced differentiation of GSCs is autophagy-dependent.
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影响因子：
14.5
作者：
Chirasani, Sridhar Reddy;Sternjak, Alexander;Glass, Rainer
通讯作者：
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