Epigenetic tumor induction by heterochromatin instability

描述(由申请人提供)：表观遗传失调和基因突变都有助于癌症的发展。虽然基因突变，如癌基因的功能获得突变和肿瘤抑制基因的功能丧失突变已经得到了广泛的研究，但表观遗传失调产生和导致癌症的机制仍然不清楚。本项目研究癌蛋白诱导异染色质失稳，从而表观遗传导致肿瘤形成的分子机制。我们建议以果蝇JAK/STAT激活的表观遗传效应为范式，研究表观遗传导致肿瘤发生的分子机制。JAK/STAT信号的异常激活与许多类型的人类癌症有关，JAK的功能获得突变已被发现导致人类白血病。JAK/STAT信号的作用很大程度上归因于STAT对促进肿瘤细胞增殖和/或存活的特定靶基因的直接转录调控。然而，我们最近在果蝇造血肿瘤模型中表明，JAK的过度激活在全球范围内扰乱了异染色质的形成，这导致了不一定是STAT直接靶点的基因的去抑制。我们进一步表明，异染色质水平对致癌JAK诱导的肿瘤形成和细胞过度增殖有很大影响。这些结果表明，异染色质失稳形式的全球表观遗传失调可能在癌症的启动和/或进展中发挥重要作用。我们假设适当的异染色质形成构成了表观遗传的肿瘤抑制机制，并且JAK/STAT信号的过度激活部分通过全局扰乱异染色质而诱导肿瘤的形成。为了验证这一假说，我们将利用果蝇的遗传系统进行遗传和生化实验，以确定JAK/STAT激活导致异染色质不稳定的分子机制，以及异染色质不稳定在肿瘤形成中的因果作用。这些研究的结果应该会促进我们对遗传和表观遗传机制如何在人类癌症发展中合作的了解，也应该会为人类癌症治疗带来新的治疗目标。公共卫生相关性：近年来，表观遗传失调在肿瘤的发生和发展中起着重要作用，受到越来越多的关注。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在表观遗传学上导致癌症发生的分子机制。这些研究的结果应该会促进我们对遗传和表观遗传机制如何在人类癌症形成中合作的了解，并可能导致癌症治疗的新治疗靶点。

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.