Role of KAT5 in lung cancer

项目总结/摘要 肺癌是美国癌症相关死亡率的主要原因。总的5年 诊断为肺癌的患者的生存率为18%，晚期患者的结局为 标准化疗已经趋于稳定受体酪氨酸基因改变的新发现 激酶如表皮生长因子受体（EGFR）已经导致酪氨酸激酶的发展 抑制剂作为肺癌治疗。然而，对抑制剂的内在和获得性抗性是目前的主要障碍。 这是临床上的一个难题，因此开发新的肺癌治疗方法势在必行。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 表观遗传细胞记忆和异常表观遗传变化与肿瘤发生有关。之间 表观遗传修饰剂，几种赖氨酸（K）乙酰转移酶（KAT）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（KAT 5）在肺癌中的功能，我们产生了 条件性Kat 5敲除小鼠，发现肺特异性Kat 5缺失抑制诱导的肿瘤形成， 通过EGFR-L 858 R-T790 M。我们还发现突变型EGFR与酪氨酸磷酸化的KAT 5结合， 催化结构域中的两个酪氨酸残基，增加其乙酰转移酶活性。因此，我们假设 KAT 5是由致癌激酶如EGFR突变体诱导的肺肿瘤发生所必需的。在目标1中， 我们将研究KAT 5酪氨酸磷酸化如何增加其乙酰化酶活性，以及是否致癌。 激酶如突变型EGFR诱导肺癌中的KAT 5活化。在目标2中，我们将研究 KAT 5调节Wnt/β-catenin信号传导，其通过激活EGFR突变对肺肿瘤发生至关重要。 此外，我们将使用生物化学分析来鉴定可能与肿瘤发生有关的KAT 5效应物 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 KAT 5是否是肿瘤起始、已建立的肺肿瘤的维持或两者所需，使用 转基因小鼠模型。目的3还提出了KAT 5在增殖和自我更新中的潜在功能 在肺癌干细胞/起始细胞中。这里提出的实验应该会导致新的表观遗传学的发展。 治疗和显著影响肺癌患者的护理，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.