Inhibition of Histone Methyltransferase EZH2 Suppresses Endometriotic Vesicle Development in a Rat Model of Endometriosis.
Inhibition of Histone Methyltransferase EZH2 Suppresses Endometriotic Vesicle Development in a Rat Model of Endometriosis.
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抑制组蛋白甲基转移酶 EZH2 可抑制子宫内膜异位症大鼠模型中子宫内膜异位囊泡的发育。
DOI：
10.1007/s43032-020-00257-9
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发表时间：
2020-09
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影响因子：
--
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中科院分区：
文献类型：
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子宫内膜异位症是一种痛苦的妇科疾病，无法治愈，治疗选择有限。表观遗传药物可用于子宫内膜异位症的非激素性治疗。本研究采用已建立的大鼠子宫内膜异位症模型，研究组蛋白甲基转移酶抑制剂EZH2的疗效。我们假设，在这个模型中，治疗将阻断或减少子宫内膜异位小泡的数量。我们在患有实验性子宫内膜异位症(子宫组织移植到肠系膜旁)或对照假手术(仅缝合)的雌性大鼠中进行了临床前药物研究。EZH2抑制剂(5 mg/kg或10 mg/kg)或赋形剂(0.1%、67%DMSO)隔日给药，共4周。治疗结束后，评估小泡的数量、面积、体积和重量。使用RT2 Profiler阵列检测神经病变和炎症、上皮细胞到间充质细胞的转变、炎症反应和自身免疫途径，以检测发育的小泡中基因表达的变化。EZH2抑制剂(10 mg/kg)通过显著减少囊泡总数、面积、体积和重量，抑制了囊泡的发育。此外，抑制EZH2显著增加了CACNA1B和FKBP1A基因的表达，这两个基因分别与疼痛和增殖有关。抑制EZH2抑制囊泡的生长，对其他器官没有明显的有害影响。用这种表观遗传抑制物治疗导致与子宫内膜异位症相关途径相关的有限数量的基因上调。总之，这些数据支持后续研究，以评估其作为治疗子宫内膜异位症的方法的潜力。
Endometriosis is a painful gynecological disease with no cure and limited therapeutic options. It has been hypothesized that epigenetic drugs can be used as a non-hormonal treatment for endometriosis. This study was conducted to study the efficacy of an inhibitor of the histone methyltransferase EZH2 using an established rat model of endometriosis. We hypothesized that treatment will block or reduce the number of endometriotic vesicles in this model. We conducted a pre-clinical drug study in female rats with experimental endometriosis (uterine tissue transplanted next to the intestinal mesentery) or control sham (sutures only). Rats with endometriosis or sham surgery received either treatment with EZH2 inhibitor (5mg/kg or 10mg/kg) or vehicle (0.1%, 67% DMSO) every other day during 4 weeks. After treatment completion, the number, area, volume, and weight of vesicles were evaluated. RT2 Profiler Arrays for Neuropathic and Inflammation, Epithelial to Mesenchymal Transition, Inflammatory Response, and Autoimmunity pathways were used to examine gene expression changes in the vesicles that developed. Treatment with EZH2 inhibitor (10 mg/kg) suppressed the development of vesicles, by significantly decreasing the total vesicle number, area, volume, and weight. In addition, EZH2 inhibition significantly increased the expression of CACNA1B and FKBP1A genes, involved in pain and proliferation, respectively. EZH2 inhibition suppresses the growth of vesicles without apparent detrimental effects to other organs. Treatment with this epigenetic inhibitor leads to upregulation of a limited number of genes related to endometriosis-relevant pathways. In conclusion, these data support follow up studies to evaluate its potential as a therapeutic approach for endometriosis.
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影响因子：
--
作者：
Ihira K;Dong P;Xiong Y;Watari H;Konno Y;Hanley SJ;Noguchi M;Hirata N;Suizu F;Yamada T;Kudo M;Sakuragi N
通讯作者：
Sakuragi N
影响因子：
2.7
作者：
Bulun SE;Cheng YH;Pavone ME;Xue Q;Attar E;Trukhacheva E;Tokunaga H;Utsunomiya H;Yin P;Luo X;Lin Z;Imir G;Thung S;Su EJ;Kim JJ
通讯作者：
Kim JJ
影响因子：
4.3
作者：
Amatangelo, Michael D.;Garipov, Azat;Zhang, Rugang
通讯作者：
Zhang, Rugang
DOI：
10.1111/1440-1681.12382
发表时间：
2015-05-01
影响因子：
2.9
作者：
Ding, Muyang;Zhang, Hang;Gao, Yane
通讯作者：
Gao, Yane
影响因子：
2.3
作者：
Liu TP;Lo HL;Wei LS;Hsiao HH;Yang PM
通讯作者：
Yang PM