Dual Role of EZH2 in Cutaneous Anaplastic Large Cell Lymphoma: Promoting Tumor Cell Survival and Regulating Tumor Microenvironment
Dual Role of EZH2 in Cutaneous Anaplastic Large Cell Lymphoma: Promoting Tumor Cell Survival and Regulating Tumor Microenvironment
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EZH2在皮肤间变性大细胞淋巴瘤中的双重作用：促进肿瘤细胞存活和调节肿瘤微环境
DOI：
10.1016/j.jid.2017.10.036
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发表时间：
2018
影响因子：
6.5
通讯作者：
Wang Y.
中科院分区：
文献类型：
--
作者：
Yi S.;Sun J.;Qiu L.;Fu W.;Wang A.;Liu X.;Yang Y.;Kadin M. E.;Tu P.;Wang Y.
原发性皮肤间变性T细胞淋巴瘤以CD 30+间变性大T细胞为特征，是皮肤T细胞淋巴瘤中第二常见的类型。对疾病进展的机制知之甚少。在这里，我们报告，增强子zeste同源物2（EZH 2），多梳抑制复合物2的催化亚基，介导组蛋白H3赖氨酸27三甲基化，是过表达的CD 30+间变性细胞在原发性皮肤间变性T细胞淋巴瘤和大细胞转化的皮肤T细胞淋巴瘤。沉默EZH 2或抑制其组蛋白甲基转移酶活性可增加体外原发性皮肤间变性T细胞淋巴瘤细胞和体内异种移植模型的细胞凋亡和G1细胞周期阻滞。这是介导的去阻遏的硫氧还蛋白相互作用蛋白，一个主要的氧化还原控制分子，和随后形成的活性氧。沉默硫氧还蛋白相互作用蛋白消除了活性氧在EZH 2抑制细胞中的积累，挽救了细胞生长劣势。此外，EZH 2抑制解除了C-X-C基序趋化因子配体10的抑制，并通过C-X-C基序趋化因子配体10/受体3相互作用促进效应CD 4+和CD 8 + T细胞募集到肿瘤微环境中。这些结果证明了多梳抑制复合物2介导的表观遗传沉默在原发性皮肤间变性T细胞淋巴瘤的肿瘤进展和抗肿瘤免疫中的双重作用，并为大细胞转化的皮肤T细胞淋巴瘤中EZH 2活性的药理学抑制提供了理论基础。
Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T-cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma.