Role of KAT5 in lung cancer

KAT5在肺癌中的作用

基本信息

批准号：
10328542
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/10328542
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 Lead Lung Lung Neoplasms Lysine Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Memory Modification Mus Mutation Oncogenic Outcome Pathway interactions Patient Care Patients Phosphotransferases Play Prognosis Progressive Disease 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 base 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/摘要肺癌是美国整体5年造成癌症相关的荒芜的主要原因诊断为肺癌的患者的存活率为18％，并且患有晚期患者的结果。标准化学疗法的遗传变化是酪氨酸的最新发现。表皮生长因子受体（EGFR）等激酶导致酪氨酸激酶的发展但是，抑制剂作为肺癌疗法。诊所中的问题，使肺癌的新疗法的发展势在必行。包含赖氨酸乙酰化，在转录激活和伸长，基因沉默和之中。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开发。有条件的Kat5敲除小鼠，发现肺特异性KAT5缺失抑制了室内肿瘤形成通过EGFR-L858R-T790M。催化域中的两个酪氨酸残基增加是乙酰转移酶的作用 KAT5是由EAM 1中的致癌激酶（例如EGFR突变体）诱导的肺肿瘤发生。我们将研究Kat5酪氨酸磷酸化的驱化酶如何以及是否致癌突变EGFR等激酶在AIM 2中诱导Kat5激活 KAT5定期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效应子加上RNA测序和染色质免疫沉淀测序的组合。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鼠标模型3还解决了Kat5的潜在功能和自我更新在肺癌茎/启动细胞中。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。