Role of KAT5 in lung cancer

项目摘要/摘要 肺癌是美国癌症相关死亡的主要原因。总体5年 被诊断为肺癌的患者存活率为18%，晚期患者接受 标准的化疗已经停滞不前。酪氨酸受体基因改变的最新发现 表皮生长因子受体(EGFR)等激酶导致酪氨酸激酶的发展 作为肺癌治疗药物的抑制剂。然而，目前对抑制剂的内在和获得性耐药是主要的 临床上存在的问题，使得肺癌的新疗法的开发势在必行。组蛋白修饰， 包括赖氨酸乙酰化，在转录激活和延伸、基因沉默和 表观遗传的细胞记忆和异常的表观遗传变化与肿瘤发生有关。其中 表观遗传修饰物，几种赖氨酸(K)乙酰转移酶(KATS)的异常活性与癌症有关 发展。为了评估其中一种乙酰转移酶(KAT5)在肺癌中的功能，我们产生了 条件性Kat5基因敲除小鼠发现肺特异的Kat5缺失抑制了诱导的肿瘤形成 由EGFR-L858R-T790M提供。我们还发现突变的EGFR与KAT5结合并被酪氨酸磷酸化。 催化区有两个酪氨酸残基，提高了其乙酰转移酶的活性。因此，我们假设 KAT5在EGFR突变体等致癌激酶诱导的肺肿瘤发生中是必需的。在目标1中， 我们将研究KAT5酪氨酸磷酸化如何增加其乙酰酶活性，以及是否致癌 突变的EGFR等激酶可诱导肺癌中KAT5的激活。在目标2中，我们将调查 KAT5通过激活表皮生长因子受体突变来调节Wnt/β-catenin信号转导，而该信号转导通路在肺肿瘤的发生中起关键作用。 此外，我们还将通过生化分析确定可能与肿瘤发生有关的KAT5效应器。 加上RNA测序和染色质免疫沉淀测序的组合。在目标3中，我们会问 无论KAT5是启动肿瘤、维持已建立的肺部肿瘤，还是两者都需要，使用 转基因小鼠模型。Aim 3还阐述了KAT5在增殖和自我更新中的潜在功能 在肺癌干细胞/启动细胞中。这里提出的实验应该会导致新的表观遗传学的发展 肺癌患者的治疗和显著影响护理，特别是那些不利的 预测，在不久的将来。

PROJECT SUMMARY/ABSTRACT Lung cancer is the leading cause of cancer-related mortality in the United States. The overall 5-year survival of patients diagnosed with lung cancer is 18%, and outcomes for advanced stage patients treated with standard chemotherapies have plateaued. Recent discoveries of genetic alterations in receptor tyrosine kinases such as Epidermal Growth Factor Receptor (EGFR) have led to development of tyrosine kinase inhibitors as lung cancer therapies. However, intrinsic and acquired resistance to inhibitors is currently a major problem in the clinic, making development of novel therapies for lung cancer imperative. Histone modifications, including lysine acetylation, play crucial roles in transcriptional activation and elongation, gene silencing and epigenetic cellular memory, and aberrant epigenetic changes are associated with oncogenesis. Among epigenetic modifiers, aberrant activity of several lysine (K) acetyltransferases (KATs) is implicated in cancer development. To assess the function of one of those acetyltransferases (KAT5) in lung cancer, we generated conditional Kat5 knockout mice and found that lung-specific Kat5 deletion suppressed tumor formation induced by EGFR-L858R-T790M. We also showed that mutant EGFR bound to and tyrosine-phosphorylated KAT5 at two tyrosine residues in the catalytic domain, increasing its acetyltransferase activity. Thus, we hypothesize that KAT5 is required for lung tumorigenesis induced by oncogenic kinases such as EGFR mutants. In Aim 1, we will investigate how KAT5 tyrosine phosphorylation increases its acetylase activity and whether oncogenic kinases such as mutant EGFR induce KAT5 activation in lung cancer. In Aim 2, we will investigate whether KAT5 regulates Wnt/β-catenin signaling, which is crucial for lung tumorigenesis by activating EGFR mutations. In addition, we will identify KAT5 effectors potentially responsible for tumorigenesis using biochemical analysis plus a combination of RNA sequencing and chromatin immunoprecipitation sequencing. In Aim 3, we will ask whether KAT5 is required for tumor initiation, maintenance of established lung tumors, or both, using transgenic mouse models. Aim 3 also addresses a potential function for KAT5 in proliferation and self-renewal in lung cancer stem/initiating cells. Experiments proposed here should lead to development of novel epigenetic therapies and significantly impact care of patients with lung cancer, particularly those with unfavorable prognosis, in the near future.