Endocrine therapies (e.g. tamoxifen and aromatase inhibitors) targeting estrogen action are effective in decreasing mortality of breast cancer. However, their efficacy is limited by intrinsic and acquired resistance. Our previous study demonstrated that overexpression of a histone methyltransferase NSD2 drives tamoxifen resistance in breast cancer cells and that NSD2 is a potential biomarker of tamoxifen resistant breast cancer. Here, we found that DZNep, an indirect inhibitor of histone methyltransferases, potently induces the degradation of NSD2 protein and inhibits the expression of NSD2 target genes (HK2, G6PD, GLUT1 and TIGAR) involved in the pentose phosphate pathway (PPP). DZNep treatment of tamoxifen-resistant breast cancer cells and xenograft tumors also strongly inhibits tumor growth and the cancer cell survival through decreasing cell production of NADPH and glutathione (GSH) and invoking elevated ROS to cause apoptosis. These findings suggest that DZNep-like agents can be developed to target NSD2 histone methyltransferase for effective treatment of tamoxifen-resistant breast cancer.

中文翻译：

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S-腺苷同型半胱氨酸（AdoHcy）依赖性甲基转移酶抑制剂DZNep通过诱导NSD2降解和抑制NSD2驱动的氧化还原稳态来克服乳腺癌他莫昔芬耐药性。

靶向雌激素作用的内分泌疗法（例如他莫昔芬和芳香酶抑制剂）可有效降低乳腺癌的死亡率。但是，它们的功效受到内在和获得性抗性的限制。我们以前的研究表明，组蛋白甲基转移酶NSD2的过表达驱动乳腺癌细胞中他莫昔芬的耐药性，而NSD2是他莫昔芬耐药性乳腺癌的潜在生物标志物。在这里，我们发现DZNep是组蛋白甲基转移酶的间接抑制剂，可有效诱导NSD2蛋白的降解并抑制戊糖磷酸途径（PPP）中涉及的NSD2目标基因（HK2，G6PD，GLUT1和TIGAR）的表达。DZNep治疗耐他莫昔芬的乳腺癌细胞和异种移植肿瘤还通过减少NADPH和谷胱甘肽（GSH）的细胞产生并调用升高的ROS引起凋亡来强烈抑制肿瘤生长和癌细胞存活。这些发现表明，可以开发DZNep样药物来靶向NSD2组蛋白甲基转移酶，以有效治疗耐他莫昔芬的乳腺癌。