Role of MYC Acetylation in Oncogenic Transformation

MYC 乙酰化在致癌转化中的作用

• 批准号: 10159869
• 负责人: ERNEST MARTINEZ
• 金额: $ 3.51万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159869
• 关键词: Acetylation; Affect; Animal Model; Antibodies; Breast Epithelial Cells; CRISPR/Cas technology; Cancer Model; Cancer cell line; Cells; Cellular biology; Chemicals; City of Hope Comprehensive Cancer Center; Clinical Trials; Collaborations; Development; EP300 gene; Embryo; Enzymes; Fibroblasts; Future; Gene Expression Regulation; Genes; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Laboratories; Lysine; MYC Family Protein; MYC gene; Maintenance; Malignant Neoplasms; Modeling; Modification; Molecular; Mutation; Normal Cell; Oncogenic; Oncoproteins; Outcome; Pathway interactions; Phenotype; Phosphorylation; Pilot Projects; Post-Translational Protein Processing; Production; Prognosis; Proto-Oncogene Proteins c-myc; RNA Interference; Rattus; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Site; Solid; Sumoylation Pathway; System; Testing; Therapeutic; Time; Tumor Cell Line; Tumor-Derived; Ubiquitination; cancer cell; cancer therapy; cancer type; cell transformation; clinical diagnostics; experimental study; histone acetyltransferase; in vivo; inhibitor/antagonist; malignant phenotype; mouse model; mutant; neoplastic cell; novel; overexpression; prognostic; response; therapeutic target; tumor; tumorigenesis

Overexpression of the MYC protein is oncogenic and commonly observed in cancer, and its inhibition induces regression of tumors in animal models. Hence, MYC is considered a promising target for cancer treatment. Besides overexpression, MYC can be deregulated by additional mechanisms, including aberrant upstream signaling pathways and posttranslational modifications (PTMs), such as phosphorylation, ubiquitination, sumoylation and acetylation that may affect the turnover and activity of the MYC protein. In particular, the functions of MYC acetylation in normal and cancer cells have remained elusive and the current information is scarce and often controversial. We propose that the limited progress and apparent discrepancies are due, in part, to (i) the fact that different histone acetyltransferases (HATs) and deacetylases (HDACs) dynamically remodel the acetyl marks on distinct lysine (K) residues of MYC in different contexts and with different outcomes, (ii) the use of pan-acetyl-lysine antibodies that do not distinguish MYC acetylation at different K residues, and (iii) the study of a limited number of in vitro cell systems/conditions that often involve artificial overexpression of HATs and may not model the signaling mechanisms leading to MYC acetylation endogenously in normal cellular contexts or in tumor cells. Hence, the relevance of MYC acetylation to normal cell biology and/or cancer development has remained largely unknown. Our laboratory has identified distinct K residues of MYC that are acetylated by different HATs and are important for specific MYC functions in selective gene regulation and transformation of rodent fibroblasts. We hypothesize that MYC acetylation is under tight regulatory control in normal cells but is deregulated in tumor-derived cancer cells and influences the oncogenic/transformation activity of MYC in human cells. To test this, Aim1 will determine whether MYC acetylation is deregulated in cancer cells by analyzing a panel of normal and cancer cell lines with acetyl-lysine site-specific antibodies and will identify specific histone deacetylase pathways that may influence site-specific MYC acetylation. Aim 2 will investigate the function of specific acetyl-lysine residues in MYC-dependent transformation of human cells and in the maintenance of the transformed phenotype of tumor-derived cancer cells. This project may uncover for the first time a deregulated acetylation of MYC at specific residues in cancer cells and establish the role of these acetylated residues in MYC-dependent transformation of human cells.

MYC蛋白的过表达是致癌的，通常在癌症中观察到， 在动物模型中其抑制诱导肿瘤消退。因此，MYC被认为是 一个很有希望的癌症治疗靶点除了过度表达，MYC还可以是 通过其他机制解除调节，包括异常的上游信号通路 和翻译后修饰（PTM），如磷酸化，泛素化， 类小泛素化和乙酰化可能影响MYC蛋白的周转和活性。 特别是，MYC乙酰化在正常和癌细胞中的功能仍然存在， 难以捉摸，目前的信息是稀缺的，往往是有争议的。我们建议 进展有限和存在明显差异的部分原因是：㈠ 不同的组蛋白乙酰转移酶（HAT）和脱乙酰酶（HDAC）动态 在不同的背景下重塑MYC的不同赖氨酸（K）残基上的乙酰基标记， 具有不同的结果，（ii）使用不能区分 MYC乙酰化在不同的K残基，和（iii）研究了有限数量的体外 通常涉及HAT的人工过表达并且可能不 模拟导致MYC乙酰化的信号传导机制， 细胞环境或肿瘤细胞中。因此，MYC乙酰化与正常 细胞生物学和/或癌症发展仍然是未知的。本实验室 已经鉴定了MYC的不同K残基，它们被不同的HAT乙酰化， MYC在选择性基因调控和转化中的特异性功能 啮齿动物成纤维细胞。我们假设MYC乙酰化受到严格的调控 在正常细胞中，但在肿瘤衍生的癌细胞中失调， MYC在人类细胞中的致癌/转化活性。为了测试这一点，Aim 1将 通过分析一组基因组来确定MYC乙酰化是否在癌细胞中失调 正常和癌细胞系与乙酰赖氨酸位点特异性抗体，并将确定 特异性组蛋白去乙酰化酶途径，可能影响位点特异性MYC乙酰化。 目的2：研究MYC依赖性细胞凋亡中特异性乙酰赖氨酸残基的功能。 转化人细胞和维持转化的表型 肿瘤衍生的癌细胞。该项目可能会首次揭示一个放松管制的 MYC在癌细胞中特定残基的乙酰化，并确定这些作用 乙酰化残基在MYC依赖性人细胞转化中的作用。