Triple-negative breast cancer (TNBC) is a heterogeneous disease with a poor prognosis due to the lack of an effective targeted therapy. Histone lysine methyltransferases (KMTs) have emerged as attractive drug targets for cancer therapy. However, the function of the majority of KMTs in TNBC has remained largely unknown. In the current study, we found that KMT nuclear receptor binding SET domain protein 2 (NSD2) is overexpressed in TNBC tumors and that its overexpression is associated with poor survival of TNBC patients. NSD2 regulates TNBC cell survival and invasion and is required for tumorigenesis and tumor growth. Mechanistically, NSD2 directly controls the expression of EGFR and ADAM9, a member of the ADAM (a disintegrin and metalloproteinase) family that mediates the release of growth factors, such as HB-EGF. Through its methylase activity, NSD2 overexpression stimulates EGFR-AKT signaling and promotes TNBC cell resistance to the EGFR inhibitor gefitinib. Together, our results identify NSD2 as a major epigenetic regulator in TNBC and provide a rationale for targeting NSD2 alone or in combination with EGFR inhibitors as a targeted therapy for TNBC.

中文翻译：

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组蛋白甲基转移酶 NSD2 通过刺激 ADAM9-EGFR-AKT 信号传导介导三阴性乳腺癌细胞的存活和侵袭。

三阴性乳腺癌（TNBC）是一种异质性疾病，由于缺乏有效的靶向治疗，预后较差。组蛋白赖氨酸甲基转移酶 (KMT) 已成为癌症治疗的有吸引力的药物靶点。然而，大多数国民党在 TNBC 中的作用仍然很大程度上未知。在目前的研究中，我们发现 KMT 核受体结合 SET 结构域蛋白 2 (NSD2) 在 TNBC 肿瘤中过度表达，并且其过度表达与 TNBC 患者的不良生存率有关。NSD2 调节 TNBC 细胞的存活和侵袭，是肿瘤发生和肿瘤生长所必需的。从机制上讲，NSD2 直接控制 EGFR 和 ADAM9 的表达，ADAM9 是 ADAM（一种去整合素和金属蛋白酶）家族的成员，可介导 HB-EGF 等生长因子的释放。通过其甲基化酶活性，NSD2 过表达刺激 EGFR-AKT 信号传导并促进 TNBC 细胞对 EGFR 抑制剂吉非替尼的耐药性。总之，我们的结果将 NSD2 确定为 TNBC 的主要表观遗传调节因子，并为单独靶向 NSD2 或与 EGFR 抑制剂联合作为 TNBC 的靶向治疗提供了依据。