Identifying the Impact of SETD2 Inactivation in Lung Adenocarcinoma

项目总结 SETD2在包括肺腺癌在内的许多癌症类型中突变失活。在出版中 工作中，我们证明了SETD2失活在自体小鼠身上具有强大的促肿瘤作用。 KrasG12D驱动的肺腺癌模型。SETD2独特的催化组蛋白H3赖氨酸36 三甲基化(H3K36me3)，标记活跃转录的基因体，促进染色质在 基因转录。在目前的项目中，我们的目标是理解SETD2的挑衅性观察 由于一碳代谢缺陷和活化，失活可潜在地推动肿瘤细胞的增殖 MTORC1信令。我们证明SETD2的缺失与S的丰度增加有关。 腺苷甲硫氨酸(SAM)和多种其他代谢物，是SAM相邻代谢途径的一部分。 我们将检验这样一种假设，即由于SETD2活性丧失而导致的SAM的停用 甲基转移酶导致SAM积聚，增强一碳代谢，激活mTORC1 信号，都支持细胞的生长和增殖。与这一假设一致，我们证明了 限制蛋氨酸饮食摄入量减少KRAS驱动的肺腺癌生长并逆转 SETD2失活的影响。因此，我们将评估针对以下目标的临床和临床前药物的疗效 蛋氨酸循环与SETD2缺乏症潜在的合成致死相互作用。最后，在下游 激活mTORC1信号我们观察到低氧诱导因子的显著转录程序 (HIF)和过氧化物酶体增殖物激活受体γ(PPARγ)共激活因子1α(Pc1α)。一如既往，我们 观察与缺氧诱导因子和前列环素α激活相关的多种病理生理变化 转录，如线粒体生物发生的改变和氧化的共同增强 磷酸化和糖酵解途径。因此，我们将测试这些母版转录的要求 影响SETD2失活下游表型的因素。

PROJECT SUMMARY SETD2 is mutationally inactivated in many cancer types including lung adenocarcinoma. In published work, we demonstrated that Setd2 inactivation has potent tumor promoting effects in an autochthonous mouse model of KRASG12D-driven lung adenocarcinoma. SETD2 uniquely catalyzes histone H3 lysine 36 trimethylation (H3K36me3), which marks actively transcribed gene bodies, facilitating chromatin resetting after gene transcription. In the current project, we aim to understand the provocative observation that SETD2 inactivation potently drives tumor cell proliferation due to a defect in one-carbon metabolism and activation of mTORC1 signaling. We demonstrate that SETD2 loss is associated with an enrichment in the abundance of S- adenosyl methionine (SAM) and multiple other metabolites that are part of SAM-adjacent metabolic pathways. We will test the hypothesis that the disuse of SAM that results from the lost activity of the SETD2 methyltransferase leads to SAM accumulation, enhanced one-carbon metabolism, and activation of mTORC1 signaling, all supporting cell growth and proliferation. Consistent with this hypothesis, we demonstrate that limiting dietary intake of methionine reduces KRAS-driven lung adenocarcinoma growth and reverses the effects of SETD2 inactivation. Thus, we will assess the efficacy of clinical and pre-clinical drugs that target the methionine cycle for potential synthetic lethal interactions with SETD2 deficiency. Finally, downstream of activated mTORC1 signaling we observe prominent transcriptional programs of hypoxia inducible factors (HIFs) and peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC1α). Consistently, we observe multiple pathophysiological changes that are associated with increased activation of HIF and PGC1α transcription, such as alterations in mitochondrial biogenesis and the co-enhancement of oxidative phosphorylation and glycolytic pathways. Thus, we will test the requirement of these master transcription factors for effectuating phenotypes downstream of SETD2 inactivation.