Targeting lysine acetyltransferase MOF/KAT8 in lung cancer

项目摘要 组蛋白和非组蛋白的动态乙酰化/去乙酰化是基因调控的关键开关 调控操纵乙酰化开关正在成为一种有前途的治疗策略， 癌症的治疗。我的实验室长期致力于阐明功能，作用机制， 和赖氨酸乙酰转移酶和脱乙酰酶的调节，探索它们在疾病中的作用， 由此产生的知识，以开发新的和更好的战略，用于治疗疾病，如癌症。的 这种重新提交申请的重点是男性缺席的第一次（MOF，也称为KAT 8或 MYST 1）蛋白，MYST赖氨酸乙酰转移酶家族的成员。MOF调节多种细胞 包括基因转录，DNA损伤反应和胚胎发育。拟议 项目是重要的，因为虽然越来越多的证据表明，财政部也密切参与， 尽管MOF与癌症密切相关，但MOF影响肿瘤发展和进展的确切机制尚不清楚。我们 初步研究揭示了MOF在上皮细胞转录抑制中的意想不到的功能， 间质转化（EMT）和细胞因子基因在肺癌中的作用。此外，MOF消耗显著增加， 由于其转录抑制的释放而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。中心假设将通过追求三个具体目标来检验：1） 剖析MOF抑制基因转录的新的和意想不到的机制; 2）研究如何 MOF通过甲基转移酶G9 a和TGF-β/SMAD控制基因表达;和3）探索M0 F的基因表达。 SIRT 1介导的MOF去乙酰化在肺癌发展中的意义的预期成果 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， 为肺癌新治疗策略的未来发展提供见解。

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.