Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.
Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, New York, USA.
JCI Insight. 2023 Feb 22;8(4):e154120. doi: 10.1172/jci.insight.154120.
SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers.
SETD2 是一种 H3K36 三甲基转移酶，是肺腺癌中最常发生突变的表观遗传修饰物，突变频率约为 9%。然而，SETD2 功能丧失如何促进肿瘤发生仍不清楚。使用条件性 Setd2-KO 小鼠，我们证明 Setd2 缺失加速了 KrasG12D 驱动的肺肿瘤发生的起始，增加了肿瘤负担，并显著降低了小鼠的存活率。综合染色质可及性和转录组分析揭示了 SETD2 的一种潜在的新型肿瘤抑制模型，其中 SETD2 缺失通过调节染色质可及性和组蛋白伴侣募集，激活内含子增强子，驱动致癌转录输出，包括 KRAS 转录特征和 PRC2 抑制的靶标。重要的是，SETD2 缺失使 KRAS 突变型肺癌对组蛋白伴侣、FACT 复合物或转录延伸的抑制作用在体外和体内均敏感。总的来说，我们的研究不仅深入了解了 SETD2 缺失如何塑造表观遗传和转录景观以促进肿瘤发生，而且还为 SETD2 突变型癌症确定了潜在的治疗策略。
