Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells.
Chromatin Remodeling Factor BRG1 Regulates Stemness and Chemosensitivity of Glioma Initiating Cells.
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DOI：
10.1002/stem.2909
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Pfeffer LM
中科院分区：
文献类型：
--
作者：
Ganguly D;Sims M;Cai C;Fan M;Pfeffer LM
多形性胶质母细胞瘤（GBM）是一种高度侵袭性和恶性的脑肿瘤，对现有的治疗方案是难治的，这反映了干细胞样细胞（称为胶质瘤起始细胞（GIC））的存在。不同信号通路之间的复杂相互作用和关键基因的表观遗传调控可能是维持GIC处于干细胞样状态的关键。虽然已经确定了几种信号通路在GBM中失调，但尽管靶向治疗有所改善，GBM患者的预后仍然很差。在这份报告中，我们确定了BRG 1，SWI/SNF染色质重塑复合物的催化亚基，在维持GIC在干细胞样状态中起着重要作用。此外，我们确定了一种新的机制，BRG 1调节糖酵解基因的关键GIC。BRG 1下调TXNIP的表达，TXNIP是糖酵解的负调节因子。BRG 1敲低还触发了STAT 3通路，这导致TXNIP激活。我们进一步确定TXNIP是一个STAT 3调控的基因。此外，BRG 1抑制干扰素刺激的基因的表达，这些基因由STAT 3负调控并调节肿瘤发生。我们进一步证明BRG 1在GIC的耐药性和GIC诱导的肿瘤发生中起着关键作用。通过遗传学和药理学手段，我们发现抑制BRG 1可以使GIC对化疗药物替莫唑胺和卡莫司汀敏感。我们的研究表明BRG 1可能是GBM的一个新的治疗靶点。BRG 1在GIC干性和化学敏感性中发挥的关键作用的鉴定将为GBM和可能的其他癌症中更好的靶向治疗的开发提供信息。
Glioblastoma multiforme (GBM) is a highly aggressive and malignant brain tumor that is refractory to existing therapeutic regimens, which reflects the presence of stem-like cells, termed glioma-initiating cells (GICs). The complex interactions between different signaling pathways and epigenetic regulation of key genes may be critical in the maintaining GICs in their stem-like state. Although several signaling pathways have been identified as being dysregulated in GBM, the prognosis of GBM patients remains miserable despite improvements in targeted therapies. In this report, we identified that BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, plays a fundamental role in maintaining GICs in their stem-like state. In addition, we identified a novel mechanism by which BRG1 regulates glycolysis genes critical for GICs. BRG1 downregulates the expression of TXNIP, a negative regulator of glycolysis. BRG1 knockdown also triggered the STAT3 pathway, which led to TXNIP activation. We further identified that TXNIP is an STAT3-regulated gene. Moreover, BRG1 suppressed the expression of interferon-stimulated genes, which are negatively regulated by STAT3 and regulate tumorigenesis. We further demonstrate that BRG1 plays a critical role in the drug resistance of GICs and in GIC-induced tumorigenesis. By genetic and pharmacological means, we found that inhibiting BRG1 can sensitize GICs to chemotherapeutic drugs, temozolomide and carmustine. Our studies suggest that BRG1 may be a novel therapeutic target in GBM. The identification of the critical role that BRG1 plays in GIC stemness and chemosensitivity will inform the development of better targeted therapies in GBM and possibly other cancers.
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DOI：
10.1016/j.bbrc.2017.07.098
发表时间：
2017-09-16
影响因子：
3.1
作者：
Du, Ziyun;Cai, Chun;Pfeffer, Lawrence M.
通讯作者：
Pfeffer, Lawrence M.
影响因子：
20.3
作者：
Buscarlet, Manuel;Krasteva, Veneta;Lessard, Julie A.
通讯作者：
Lessard, Julie A.
影响因子：
1.1
作者：
Gutenberg, A.;Bock, H. C.;Giese, A.
通讯作者：
Giese, A.
影响因子：
8
作者：
Glaros, S.;Cirrincione, G. M.;Reisman, D.
通讯作者：
Reisman, D.
影响因子：
14.9
作者：
Flanagan, JF;Peterson, CL
通讯作者：
Peterson, CL