Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells.
Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells.
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DOI：
10.1186/s12885-018-4874-8
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发表时间：
2018-10-22
期刊：
影响因子：
3.8
通讯作者：
Xia S
中科院分区：
文献类型：
--
作者：
Tung B;Ma D;Wang S;Oyinlade O;Laterra J;Ying M;Lv SQ;Wei S;Xia S
胶质母细胞瘤(GBM)患者预后不良的原因是一种罕见的肿瘤干细胞亚群，这些干细胞表现出肿瘤起始、生长和对化疗和伴随放疗的侵袭性治疗耐药的特点。最近对表观遗传机制在癌症发病机制中的重要作用的研究促使了对组蛋白的酶修饰用于治疗药物靶向的研究。在这项工作中，我们研究了转录因子Krüppel-like factor9(KLF9)在组蛋白脱乙酰酶抑制剂(HDAC抑制剂)化疗增敏中的作用。由于患者来源的胶质瘤的GBM神经球培养富含GBM干细胞(GSCs)，并形成高度侵袭性和增殖性的异种移植，概括了诊断为GBM的人类患者的特征，因此我们在这些GBM神经球细胞中建立了可诱导的KLF9表达系统，并研究了在组蛋白脱乙酰酶(HDAC)抑制剂等表观遗传调节剂存在的情况下细胞死亡。我们证明，KLF9的表达与HDAC抑制剂Panobinostat(LBH589)以协同的方式显著诱导胶质瘤干细胞通过凋亡和坏死下垂而死亡。KLF9的表达与LBH589联合作用可显著降低S期细胞的比例，从而影响细胞周期。细胞周期抑制因子p21和p27的上调进一步证实了这一现象。此外，我们确定KLF9和LBH589调节促凋亡和抗凋亡蛋白的表达，提示了一种涉及caspase依赖的凋亡途径的机制。此外，我们还证明了细胞凋亡和坏死抑制剂对细胞死亡的保护作用很小，而坏死性下垂途径的抑制剂则显著阻止了细胞死亡。我们的发现表明，详细了解KLF9在具有表观遗传调节剂(如HDAC抑制剂)的癌细胞中的表达如何通过涉及细胞凋亡和坏死下垂的机制促进协同细胞死亡，这将有助于新的联合抗肿瘤策略治疗恶性脑瘤。
The dismal prognosis of patients with glioblastoma (GBM) is attributed to a rare subset of cancer stem cells that display characteristics of tumor initiation, growth, and resistance to aggressive treatment involving chemotherapy and concomitant radiation. Recent research on the substantial role of epigenetic mechanisms in the pathogenesis of cancers has prompted the investigation of the enzymatic modifications of histone proteins for therapeutic drug targeting. In this work, we have examined the function of Krüppel-like factor 9 (KLF9), a transcription factor, in chemotherapy sensitization to histone deacetylase inhibitors (HDAC inhibitors). Since GBM neurosphere cultures from patient-derived gliomas are enriched for GBM stem-like cells (GSCs) and form highly invasive and proliferative xenografts that recapitulate the features demonstrated in human patients diagnosed with GBM, we established inducible KLF9 expression systems in these GBM neurosphere cells and investigated cell death in the presence of epigenetic modulators such as histone deacetylase (HDAC) inhibitors. We demonstrated that KLF9 expression combined with HDAC inhibitor panobinostat (LBH589) dramatically induced glioma stem cell death via both apoptosis and necroptosis in a synergistic manner. The combination of KLF9 expression and LBH589 treatment affected cell cycle by substantially decreasing the percentage of cells at S-phase. This phenomenon is further corroborated by the upregulation of cell cycle inhibitors p21 and p27. Further, we determined that KLF9 and LBH589 regulated the expression of pro- and anti- apoptotic proteins, suggesting a mechanism that involves the caspase-dependent apoptotic pathway. In addition, we demonstrated that apoptosis and necrosis inhibitors conferred minimal protective effects against cell death, while inhibitors of the necroptosis pathway significantly blocked cell death. Our findings suggest a detailed understanding of how KLF9 expression in cancer cells with epigenetic modulators like HDAC inhibitors may promote synergistic cell death through a mechanism involving both apoptosis and necroptosis that will benefit novel combinatory antitumor strategies to treat malignant brain tumors.
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通讯作者：
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