Targeting lysine acetyltransferase MOF/KAT8 in lung cancer

靶向赖氨酸乙酰转移酶 MOF/KAT8 在肺癌中的作用

基本信息

批准号：
10601761
负责人：
EDWARD SETO
金额：
$ 39.52万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601761
关键词：
Acetylation Acetyltransferase Adenocarcinoma Cell Affect Binding Cancer Etiology Cancer Prognosis Cell physiology Cessation of life Complex Cytokine Gene DNA Damage Data Data Set Deacetylase Deacetylation Development Disease Embryonic Development Enzymes Epithelium Event Family Future Gene Expression Gene Expression Regulation Genes Genetic Transcription HDAC2 gene Histone Deacetylation Histone H4 Histones Immunohistochemistry KRAS2 gene Knock-in Mouse Knock-out Laboratories Link Lung Lung Adenocarcinoma Lysine MADH4 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Methyltransferase Molecular Outcome Patient-Focused Outcomes Patients Play Post-Translational Protein Processing Process Proteins Regulation Repressor Proteins Research Role SIRT1 gene Science Signal Transduction Site TP53 gene Testing The Cancer Genome Atlas Therapeutic Tissues Transcription Repressor Transforming Growth Factor beta Ubiquitination United States Woman Work cancer diagnosis cancer therapy epithelial to mesenchymal transition gene repression improved insight interest knowledge of results loss of function lung health lung tumorigenesis male member men mouse model non-histone protein novel novel therapeutic intervention promoter protein function response survival outcome therapeutic target transcriptome sequencing treatment strategy tumor

项目摘要

Project Summary Dynamic acetylation/deacetylation of histones and nonhistone proteins is a critical switch in gene regulation. Manipulation of the acetylation switch is emerging as a promising therapeutic strategy in the treatment of cancer. My laboratory has a long-term interest in clarifying the functions, mechanisms of action, and regulation of lysine acetyltransferases and deacetylases, exploring their roles in diseases, and using the resulting knowledge to develop new and better strategies for the treatment of diseases such as cancer. The key focus of this resubmission application is on the Males Absent on the First (MOF, also called KAT8 or MYST1) protein, a member of the MYST lysine acetyltransferase family. MOF regulates a variety of cellular processes including gene transcription, DNA damage responses, and embryonic development. The proposed project is significant because although increasing evidence suggests that MOF is also closely involved in cancer, the exact mechanism by which MOF impacts tumor development and progression is unclear. Our preliminary studies revealed an unexpected function of MOF in the transcriptional repression of epithelial to mesenchymal transition (EMT) and cytokine genes in lung cancer. Furthermore, MOF depletion significantly affects lung tumorigenesis in mouse models due to release of its transcriptional repression. Based on these exciting preliminary results, we hypothesize that MOF may be a potential target for treatments of lung cancer. The long-term objective is to explore how MOF regulates uncharacterized gene expression and signaling processes to impact lung cancer. The central hypothesis will be tested by pursuing three specific aims: 1) Dissect the novel and unexpected mechanisms by which MOF represses gene transcription; 2) Examine how MOF controls gene expression via the methyltransferase G9a and TGF-beta/SMAD; and 3) Explore the implications of SIRT1-mediated deacetylation of MOF in lung cancer development. The expected outcome of this work will help elucidate new functions of MOF and its mechanisms of action in lung tumorigenesis, and provide insights into future development of new therapeutic strategies for lung cancer.

项目概要组蛋白和非组蛋白的动态乙酰化/去乙酰化是基因的关键转换规定。乙酰化开关的操纵正在成为一种有前途的治疗策略癌症的治疗。我的实验室对阐明其功能、作用机制有着长期的兴趣，赖氨酸乙酰转移酶和脱乙酰酶的研究和调节，探索它们在疾病中的作用，并利用由此产生的知识可以开发新的、更好的策略来治疗癌症等疾病。这此重新提交申请的重点是第一名缺席的男性（MOF，也称为 KAT8 或 MYST1) 蛋白，MYST 赖氨酸乙酰转移酶家族的成员。 MOF 调节多种细胞过程包括基因转录、DNA 损伤反应和胚胎发育。拟议的该项目意义重大，因为尽管越来越多的证据表明财政部也密切参与癌症中，MOF 影响肿瘤发生和进展的确切机制尚不清楚。我们的初步研究揭示了 MOF 在上皮细胞转录抑制中的意外功能肺癌中的间质转化（EMT）和细胞因子基因。此外，MOF 的消耗显着由于其转录抑制的释放，影响小鼠模型中的肺肿瘤发生。基于这些令人兴奋的初步结果，我们假设 MOF 可能是治疗肺癌的潜在靶点。长期目标是探索 MOF 如何调节未表征的基因表达和信号传导影响肺癌的过程。将通过追求三个具体目标来检验中心假设：1）剖析 MOF 抑制基因转录的新颖且意想不到的机制； 2）检查如何 MOF 通过甲基转移酶 G9a 和 TGF-β/SMAD 控制基因表达； 3) 探索 SIRT1 介导的 MOF 脱乙酰化在肺癌发展中的影响。预期结果这项工作将有助于阐明 MOF 的新功能及其在肺肿瘤发生中的作用机制，以及为肺癌新治疗策略的未来发展提供见解。