Epigenetic tumor induction by heterochromatin instability

异染色质不稳定性诱导表观遗传肿瘤

• 批准号: 8193217
• 负责人: WILLIS X LI
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193217
• 关键词: Attention; Binding; Biochemical; Cancer Etiology; Cell Proliferation; Cells; Chromatin Structure; Confocal Microscopy; DNA Binding; Development; Drosophila genus; Epigenetic Process; Euchromatin; Event; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Global Change; Goals; Grant; Health; Hematopoietic Neoplasms; Heterochromatin; Human; Knowledge; Lead; Malignant Neoplasms; Modeling; Molecular; Oncogene Proteins; Oncogenes; Oncogenic; Pattern; Phosphorylation; Phosphotransferases; Play; Process; Role; Signal Pathway; Signal Transduction; Site; System; Testing; Time; Transcriptional Regulation; Transgenes; Translations; Tumor Suppression; Tumor Suppressor Proteins; cancer initiation; cancer therapy; chromatin modification; derepression; gain of function mutation; heterochromatin-specific nonhistone chromosomal protein HP-1; insight; leukemia; loss of function mutation; molecular dynamics; mutant; neoplastic cell; new therapeutic target; research study; response; time use; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Epigenetic dysregulation and genetic mutations both contribute to cancer development. While genetic mutations such as gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressors have been extensively studied, the mechanisms by which epigenetic dysregulation arises and causes cancers remain obscure. This project investigates the molecular mechanisms by which oncoproteins induce heterochromatin destabilization, thereby epigenetically causing tumor formation. We propose to use the epigenetic effects of JAK/STAT activation in Drosophila as a paradigm to study the molecular mechanisms of epigenetic causes of tumorigenesis. Aberrant activation of JAK/STAT signaling is associated with many types of human cancers, and gain-of-function mutations in JAK have been identified that cause human leukemia. The effects of JAK/STAT signaling have been attributed largely to direct transcriptional regulation by STAT of specific target genes that promote tumor cell proliferation and/or survival. We have recently shown in a Drosophila hematopoietic tumor model, however, that JAK overactivation globally disrupts heterochromatin formation, which leads to derepression of genes that are not necessarily direct targets of STAT. We have further shown that heterochromatin levels greatly influence oncogenic JAK-induced tumor formation and cell overproliferation. These results suggest that global epigenetic dysregulation in the form of heterochromatin destabilization may play an essential role in cancer initiation and/or progression. We hypothesize that proper heterochromatin formation constitutes an epigenetic tumor suppression mechanism, and that overactivation of JAK/STAT signaling induces tumor formation in part by globally disrupting heterochromatin. To test this hypothesis, we will take advantage of the Drosophila genetic system to carry out genetic and biochemical experiments to determine the molecular mechanisms by which JAK/STAT activation leads to heterochromatin instability, and the causal role of heterochromatin destabilization in tumor formation. Results from these studies should advance our knowledge of how genetic and epigenetic mechanisms cooperate in cancer development in humans and should also lead to new therapeutic targets for human cancer treatment. PUBLIC HEALTH RELEVANCE: Epigenetic dysregulation has received increasing attention in recent years as playing important roles in tumor initiation and progression. The overall goal of this project is to elucidate the molecular mechanism by which oncoprotein-induced heterochromatin instability epigenetically causes cancer development. Results from these studies should advance our knowledge of how genetic and epigenetic mechanisms cooperate in cancer formation in humans and could also lead to new therapeutic targets for cancer treatment.

描述（由申请人提供）：表观遗传失调和遗传突变都有助于癌症的发展。尽管已经广泛研究了肿瘤基因中的遗传突变，例如肿瘤基因中的功能突变和肿瘤抑制剂的功能丧失突变，但出现表观遗传失调的机制，导致原因癌症造成的癌症仍然晦涩难懂。该项目研究了癌蛋白诱导异染色质不稳定的分子机制，从而表观遗传引起肿瘤的形成。我们建议将果蝇中JAK/Stat激活的表观遗传作用作为研究肿瘤发生表观遗传原因的分子机制的范例。 JAK/STAT信号的异常激活与许多类型的人类癌症有关，并且已经确定了引起人类白血病的JAK的功能收益突变。 JAK/Stat信号的效果主要归因于促进肿瘤细胞增殖和/或存活的特定靶基因的指定转录调控。然而，我们最近在果蝇造血肿瘤模型中显示，JAK过度活化在全球范围内破坏了异染色质的形成，这导致了不一定是STAT的直接靶标的基因消除。我们进一步表明，异染色质水平极大地影响致癌JAK诱导的肿瘤形成和细胞过度增殖。这些结果表明，以异染色质不稳定形式形式的全球表观遗传失调可能在癌症开始和/或进展中起着至关重要的作用。我们假设适当的异染色质形成构成了表观遗传肿瘤抑制机制，而JAK/Stat信号传导过度激活过度激活肿瘤形成部分通过全球扰乱的异染色质。为了检验这一假设，我们将利用果蝇遗传系统进行遗传和生化实验，以确定JAK/Stat活化导致异染色质不稳定性的分子机制，以及肿瘤形成中异淋巴结蛋白衰弱的因果作用。这些研究的结果应提高我们对人类癌症发展中遗传和表观遗传机制如何合作的了解，还应为人类癌症治疗带来新的治疗靶标。公共卫生相关性：近年来，表观遗传失调引起了人们的关注，因为在肿瘤的启动和进展中发挥了重要作用。该项目的总体目标是阐明癌蛋白诱导的异染色质不稳定性表观遗传性引起癌症发展的分子机制。这些研究的结果应提高我们对人类癌症形成中遗传和表观遗传机制如何合作的了解，并且还可能导致新的治疗靶标。