Unique anti-glioblastoma activities of hypericin are at the crossroad of biochemical and epigenetic events and culminate in tumor cell differentiation.
Unique anti-glioblastoma activities of hypericin are at the crossroad of biochemical and epigenetic events and culminate in tumor cell differentiation.
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DOI：
10.1371/journal.pone.0073625
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lavie G
中科院分区：
文献类型：
--
作者：
Dror N;Mandel M;Lavie G
传统疗法未能缓解胶质母细胞瘤（GBM）促进寻找新的治疗策略。这些包括表观遗传调节剂，如组蛋白脱乙酰酶抑制剂（HDACi），其放松异常紧凑的肿瘤细胞染色质组织，使细胞能够克服分化障碍。然而，在临床环境中，HDACi疗效仅限于血液恶性肿瘤的子集。我们推断靶向多种表观遗传机制的分子可能表现出上级抗癌活性。我们专注于氧化还原的苝醌金丝桃素（HYP），并表明HYP靶向热休克蛋白90的多聚泛素化，降解和失活。热休克蛋白90参与介导可遗传的表观遗传修饰转移到后代。因此，我们检查了HYP是否可以诱导GBM细胞中的表观遗传学改变，并在此显示HYP确实通过独特的方式靶向人类胶质母细胞瘤肿瘤细胞系中的多种机制。这些引起关键发育调控基因的主要表观遗传特征变化。HYP诱导神经胶质肿瘤细胞分化，调节细胞结构，神经胶质分化抗原表达，并导致退出细胞增殖周期。这些活性表征HDACi，然而HYP不是HDAC抑制剂。相反，HYP有效地下调I类HDAC的表达，在HDAC细胞内容物中产生显著缺陷，导致组蛋白H3和H4超乙酰化。EZH 2的表达也受到抑制，EZH 2是Polycomb阻遏复合物-2催化亚基，它使组蛋白H3 K27三甲基化。由此产生的组蛋白超乙酰化和减少的H3 K27-三甲基化松弛染色质结构，激活基因转录，包括分化促进基因。DNMT谱也被调节，增加整体DNA甲基化。HYP诱导HDAC、EZH 2和DNMT的独特表观遗传下调，重塑染色质结构并最终导致肿瘤细胞分化。这些调节产生在复发性、进行性疾病患者中进行的临床试验中获得的临床显著的抗GBM作用。尽管疾病处于晚期，但患者对HYP有反应，表现出稳定的疾病和部分反应;接受同情治疗的患者存活长达34个月。金丝桃素可能构成一种新的抗胶质母细胞瘤治疗模式。
Failure of conventional therapies to alleviate glioblastoma (GBM) fosters search for novel therapeutic strategies. These include epigenetic modulators as histone deacetylase inhibitors (HDACi), which relax abnormally compact tumor cell chromatin organization, enabling cells to overcome blockage in differentiation. However, in clinical settings, HDACi efficacy is confined to subsets of hematologic malignancies. We reasoned that molecules targeting multiple epigenetic mechanisms may exhibit superior anti-cancer activities. We focused on the redox perylene-quinone Hypericin (HYP) and showed that HYP targets Hsp90 for polyubiquitination, degradation and inactivation. Hsp90 is implicated in mediating inheritable epigenetic modifications transferable to progeny. We therefore examined if HYP can induce epigenetic alterations in GBM cells and show here that HYP indeed, targets multiple mechanisms in human glioblastoma tumor cell lines via unique manners. These elicit major epigenetic signature changes in key developmentally regulated genes. HYP induces neuroglial tumor cell differentiation modulating the cytoarchitecture, neuroglial differentiation antigen expression and causes exit from cell proliferation cycles. Such activities characterize HDACi however HYP is not an HDAC inhibitor. Instead, HYP effectively down-regulates expression of Class-I HDACs, creating marked deficiencies in HDACs cellular contents, leading to histones H3 and H4 hyperacetylation. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3K27 is also suppressed. The resulting histone hyperacetylation and diminished H3K27-trimethylation relax chromatin structure, activating gene transcription including differentiation-promoting genes. DNMT profiles are also modulated increasing global DNA methylation. HYP induces unique epigenetic down-regulations of HDACs, EZH2 and DNMTs, remodeling chromatin structure and culminating in tumor cell differentiation. These modulations generate clinically significant anti-GBM effects obtained in a clinical trial performed in patients with recurrent, progressive disease. Despite this advanced disease stage, patients responded to HYP, displaying stable disease and partial responses; patients on compassionate therapy survived for up to 34 months. Hypericin may constitute a novel anti-glioblastoma therapeutic paradigm.
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影响因子：
2.2
作者：
KEISARI, Y
通讯作者：
KEISARI, Y
影响因子：
6.7
作者：
Kim, JI;Park, JH;Lee, KT
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11.2
作者：
Cadieux, Benoit;Ching, Tsui-Ting;Costello, Joseph F.
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15
作者：
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3.3
作者：
REDEPENNING, J;TAO, NB
通讯作者：
TAO, NB