实体肿瘤的一项普遍特征是低氧水平，即所谓的缺氧，它在化学耐药中扮演着关键角色。表观遗传机制，如DNA甲基化和组蛋白修饰，参与了癌症的发展和进展。有大量证据表明，表观遗传药物在正常氧气水平下（即常氧）可以逆转癌细胞获得的耐药性。然而，尚不清楚表观遗传药物是否可以改善缺氧条件下获得的耐药性。本研究旨在探讨表观遗传药物是否可以改善缺氧条件下癌细胞的耐药性。我们在小鼠黑色素瘤B16-BL6（B16）细胞中发现，在缺氧条件下（1％O2），低氧诱导因子1α（HIF-1α）及其靶基因的表达增加。在B16细胞中，缺氧条件下对7-乙基-10-羟基紫杉醇替诺酮盐（SN-38，即伊立替康的活性代谢产物）的耐药性也得到了获得。此外，作为表观遗传机制，增强子酶同源物2（EZH2）的蛋白表达和其靶基因组蛋白H3赖氨酸27位点的三甲基化（H3K27Me3）水平在缺氧条件下增加。H3K27Me3的诱导在缺氧条件下被EZH2小RNA和3-deazaneplanocin A（DZNep，EZH2抑制剂）所抑制。此外，EZH2小RNA和DZNep在SN-38处理后显著降低了细胞存活率，并在缺氧条件下改善了对SN-38的耐药性。这些结果表明，缺氧条件下对SN-38的耐药性可能源于表观遗传机制，即由于EZH2的诱导而导致H3K27Me3的升高。总之，组蛋白甲基转移酶EZH2抑制剂DZNep能够通过抑制在缺氧肿瘤微环境中引起的组蛋白甲基化来解决获得性耐药性问题。版权所有 © 2023 Elsevier Inc.。保留所有权利。

One of common characteristics of solid tumors is low O2 level, so-called hypoxia, which plays a critical role in chemoresistance. Epigenetic mechanism such as DNA methylation and histone modification is involved in cancer development and progression. There is ample evidence that epigenetic drugs reversed acquired chemoresistance in cancer cells under normal O2 level, normoxia. However, it remains unknown whether epigenetic drugs improve acquired chemoresistance under hypoxia. The aim of our study was to investigate whether epigenetic drugs can improve the chemoresistance induced under hypoxia in cancer cells. In murine melanoma B16-BL6 (B16) cells, the culture under hypoxia, 1%O2 caused the elevated expression of hypoxia-inducible factor-1α (HIF-1α) and its target genes. The chemoresistance to 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) was also acquired under hypoxia in B16 cells. In addition, as epigenetic mechanisms, the protein expression of the enhancer of zeste homolog 2 (EZH2), histone methyltransferase and its target histone H3 trimethylation at lysine 27 (H3K27Me3) level increased under hypoxia. The induction of H3K27Me3 under hypoxia was suppressed by EZH2 siRNA and 3-deazaneplanocin A (DZNep), an EZH2 inhibitor. Furthermore, both EZH2 siRNA and DZNep significantly reduced the cell viability after SN-38 treatment and improved the chemoresistance to SN-38 under hypoxia. These results indicated that the chemoresistance to SN-38 under hypoxia would arise from epigenetic mechanism, H3K27Me3 elevation due to EZH2 induction. In conclusion, a histone methyltransferase EZH2 inhibitor, DZNep was capable of tackling acquired chemoresistance via the suppression of histone methylation induced under hypoxic tumor microenvironment.Copyright © 2023 Elsevier Inc. All rights reserved.