Role of MYC Acetylation in Oncogenic Transformation

MYC蛋白的过度表达是致癌的，通常在癌症中观察到，并且 其抑制作用可诱导动物模型肿瘤的消退。因此，MYC被认为是 这是癌症治疗的一个有希望的靶点。除了过度表达，MYC还可以 通过其他机制解除管制，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、 苏莫化和乙酰化可能影响MYC蛋白的周转和活性。 特别是，MYC乙酰化在正常细胞和癌细胞中的功能仍然存在 难以捉摸，目前的信息很稀少，而且往往有争议。我们建议 进展有限和出现明显差异的部分原因是：(一) 不同的组蛋白乙酰转移酶(HATS)和脱乙酰酶(HDAC)的动态变化 在不同环境中重塑MYC不同赖氨酸(K)残基上的乙酰标记 有不同的结果，(Ii)使用泛乙酰赖氨酸抗体 MYC在不同K残基上的乙酰化，以及(III)有限数量的体外研究 细胞系统/条件，通常涉及人为过表达HATS，可能不 正常大鼠内源性MYC乙酰化信号机制的模拟 细胞环境或肿瘤细胞中。因此，MYC乙酰化与正常的相关性 细胞生物学和/或癌症的发展在很大程度上仍然是未知的。我们的实验室 已经确定了不同HAT乙酰化的MYC的不同K残基，并且是 特定的MYC功能在植物选择性基因调控和转化中的重要作用 啮齿动物成纤维细胞。我们假设MYC乙酰化受到严格的监管。 但在肿瘤来源的癌细胞中却被解除了调控，并影响了 MYC在人细胞中的致癌/转化活性。为了测试这一点，Aim1将 通过分析一个小组来确定癌细胞中的MYC乙酰化是否被解除调控 具有乙酰赖氨酸位点特异性抗体的正常和癌细胞株，并将识别 可能影响特定部位MYC乙酰化的特异组蛋白去乙酰化途径。 目的2研究特定的乙酰赖氨酸残基在MYC依赖中的作用 人类细胞的转化和保持转化后的表型 肿瘤来源的癌细胞。这个项目可能会首次揭开一个放松管制的 癌细胞中特定残基上MYC的乙酰化及其作用 依赖myc的人类细胞转化中的乙酰化残基。

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.