Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Nat Cancer. 2022 Jun;3(6):753-767. doi: 10.1038/s43018-022-00361-6. Epub 2022 Apr 21.
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.
小细胞肺癌（SCLC）以其早期和频繁的转移而臭名昭著，这使其成为一种难治性恶性肿瘤。为了了解 SCLC 转移的分子机制，我们生成了具有原位移植基因组编辑肺类器官的 SCLC 小鼠模型，并进行了多组学分析。我们发现，组蛋白 H3 赖氨酸 4 甲基转移酶 KMT2C 的缺失（在广泛期 SCLC 中经常发生突变）促进了小鼠的多器官转移。转移和 KMT2C 缺陷的 SCLC 均表现出组蛋白和 DNA 低甲基化。从机制上讲，KMT2C 通过组蛋白甲基化直接调节从头 DNA 甲基转移酶 DNMT3A 的表达。强制表达 DNMT3A 通过抑制促进转移的 MEIS/HOX 基因来抑制 KMT2C 缺陷型 SCLC 的转移。此外，组蛋白和 DNA 甲基转移酶的共同辅因子 S-（5'-腺苷基）-L-蛋氨酸抑制 SCLC 转移。因此，我们的研究揭示了 KMT2C 和 DNMT3A 介导的组蛋白和 DNA 低甲基化的协同表观遗传重编程是 SCLC 转移的基础，这提示了一种潜在的表观遗传治疗弱点。
