Role of KAT5 in lung cancer

KAT5在肺癌中的作用

基本信息

批准号：
10548187
负责人：
Susumu Kobayashi
金额：
$ 39.12万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548187
关键词：
Acetylation Acetylesterase Acetyltransferase Address Binding Biochemical Cancer Etiology Candidate Disease Gene Catalytic Domain Cell model Cells ChIP-seq Clinic Clonal Evolution Data Development Diagnosis EGFR gene Epidermal Growth Factor Receptor Epigenetic Process Future Gene Silencing Genes Goals HTATIP gene Histone Acetylation Human Immunotherapy In Vitro Individual Knock-out Knockout Mice Lung Lung Neoplasms Lysine Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Memory Modification Mus Mutation Oncogenic Outcome Pathway interactions Patient Care Patients Phosphorylation Phosphotransferases Play Prognosis Progressive Disease Proliferating Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Recurrence Reporting Resistance Role Sampling Signal Pathway Signal Transduction Testing Time Transcription Elongation Transcriptional Activation Transgenic Mice Tyrosine Tyrosine Kinase Inhibitor Tyrosine Phosphorylation United States beta catenin cancer therapy chemotherapy driver mutation epigenetic therapy experimental study histone modification in vivo inhibitor knock-down lung cancer cell lung development lung tumorigenesis mortality mouse model mutant new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics receptor binding self-renewal stem targeted treatment transcriptome sequencing tumor tumor growth tumor heterogeneity tumor initiation tumorigenesis

项目摘要

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.

项目摘要/摘要肺癌是美国与癌症相关死亡率的主要原因。整体五年诊断为肺癌的患者的存活率为18％，治疗治疗的晚期阶段患者的结果标准化学疗法已经平稳。最近发现受体酪氨酸遗传改变的发现表皮生长因子受体（EGFR）等激酶导致酪氨酸激酶的发展抑制剂作为肺癌疗法。但是，目前对抑制剂的固有和获得的抗性是主要的诊所中的问题，使肺癌的新疗法的发展势在必行。组蛋白修饰，包括赖氨酸乙酰化，在转录激活和伸长，基因沉默和表观遗传性细胞记忆和异常表观遗传变化与肿瘤发生有关。之中表观遗传修饰剂，几种赖氨酸（K）乙酰基转移酶（KAT）的异常活性与癌症有关发展。为了评估其中一种乙酰基转移酶（Kat5）在肺癌中的功能，我们产生了有条件的Kat5敲除小鼠，发现肺特异性KAT5缺失抑制了肿瘤的形成由EGFR-L858R-T790M。我们还表明，突变体EGFR与AT的抑制剂和酪氨酸磷酸化的Kat5结合两种酪氨酸保留在催化结构域中，增加了其乙酰转移酶活性。那我们假设该KAT5是由EGFR突变体等致癌激酶诱导的肺肿瘤发生所必需的。在AIM 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EGFR等激酶在肺癌中诱导KAT5激活。在AIM 2中，我们将调查是否 KAT5调节Wnt/β-catenin信号传导，这对于通过激活EGFR突变而对肺肿瘤发生至关重要。此外，我们将使用生化分析确定可能导致肿瘤发生的Kat5效应器加上RNA测序和染色质免疫沉淀测序的组合。在AIM 3中，我们会问是否需要KAT5肿瘤启动，维持已建立的肺肿瘤或两者兼有转基因小鼠模型。 AIM 3还解决了Kat5在增殖和自我更新方面的潜在功能在肺癌茎/引发细胞中。这里提出的实验应导致新型表观遗传的发展疗法并显着影响肺癌患者的护理，尤其是那些不利的患者预后，不久的将来。