Resistance to chemotherapy remains a critical barrier to effective cancer treatment. Although cisplatin is one of the most commonly used chemotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC), mechanisms of resistance to this drug are not fully understood. Here, we report a novel cisplatin-resistance mechanism involving SET Domain Containing 2 (SETD2), a histone H3 lysine 36 (H3K36) trimethyltransferase, and cAMP-responsive element-binding protein 1 (CREB1). A549 cells selected in vivo to give brain metastases exhibited cisplatin resistance and decreased expression of phosphorylated CREB1. Next-generation sequencing (NGS) analysis identified a missense mutation in SETD2 (p.T1171K), and we demonstrated that SETD2-mediated trimethylation of H3K36 (H3K36me3) and CREB1 phosphorylation are critical for cellular sensitivity to cisplatin. Moreover, we showed that suppression of SETD2 or CREB1 and ectopic expression of mutant SETD2 conferred cisplatin resistance through inhibition of H3K36me3 and ERK activation in NSCLC cells. Our results provide evidence that SETD2 and CREB1 contribute to cisplatin cytotoxicity via regulation of the ERK signaling pathway, and their inactivation may lead to cisplatin resistance.

中文翻译：

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获得性 SETD2 突变和受损的 CREB1 激活赋予转移性非小细胞肺癌顺铂耐药性。

对化疗的耐药性仍然是有效治疗癌症的关键障碍。尽管顺铂是治疗非小细胞肺癌 (NSCLC) 中最常用的化疗药物之一，但对该药物的耐药机制尚不完全清楚。在这里，我们报告了一种新的顺铂耐药机制，涉及 SET Domain Containing 2 (SETD2)、组蛋白 H3 赖氨酸 36 (H3K36) 三甲基转移酶和 cAMP 响应元件结合蛋白 1 (CREB1)。体内选择产生脑转移的 A549 细胞表现出顺铂耐药性和磷酸化 CREB1 的表达降低。下一代测序 (NGS) 分析确定了 SETD2 (p.T1171K) 中的错义突变，我们证明了 SETD2 介导的 H3K36 三甲基化 (H3K36me3) 和 CREB1 磷酸化对于细胞对顺铂的敏感性至关重要。此外，我们发现抑制 SETD2 或 CREB1 和突变 SETD2 的异位表达通过抑制 NSCLC 细胞中的 H3K36me3 和 ERK 活化赋予顺铂耐药性。我们的结果提供证据表明 SETD2 和 CREB1 通过调节 ERK 信号通路促进顺铂细胞毒性，并且它们的失活可能导致顺铂耐药。