文章目录

KMT2C缺陷通过dnmt3a介导的表观遗传重编程促进小细胞肺癌转移

原文发布日期：2022-04-21

英文摘要：

摘要翻译：

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文章：

KMT2C缺陷通过dnmt3a介导的表观遗传重编程促进小细胞肺癌转移

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming

原文发布日期：2022-04-21

英文摘要：

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5′-adenosyl)-l-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

摘要翻译：

小细胞肺癌（SCLC）以其早期和频繁转移而闻名，这使它成为难以治疗的恶性肿瘤。为了理解SCLC转移的分子机制，我们通过正位移植基因编辑肺器官组织块并进行多组学分析，构建了SCLC小鼠模型。我们发现，KMT2C缺乏——广泛期SCLC中常被突变的组蛋白H3甲基化酶——促进了小细胞肺癌在小鼠中的多器官转移。转移性SCLC和KMT2C缺陷型SCLC均显示出组蛋白和DNA甲基化减低。机制上，KMT2C通过组蛋白甲基化直接调节DNMT3A的表达（DNMT3A是一种新基因甲基化的组蛋白转录酶），从而调控了DNA甲基化。进一步地， forced DNMT3A的表达通过抑制促进转移的MEIS和HOX基因而限制了KMT2C缺陷型SCLC的转移。此外，S-（5'-腺苷酰）L-甲硫氨酸——组蛋白甲基化酶和DNA甲基化酶的共同辅因子——抑制了小细胞肺癌的转移。因此，我们研究揭示了通过KMT2C和DNMT3A介导的历史和基因甲基化 epigenetic 重新编程的小细胞肺癌转移的基础机制，这表明存在潜在的epigenetic治疗易变性。