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均有助于癌症发展。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被广泛研究，表观遗传失调引起癌症的机制仍然不清楚。本项目研究癌蛋白诱导异染色质不稳定，从而表观遗传导致肿瘤形成的分子机制。我们建议使用JAK/STAT激活在果蝇的表观遗传效应作为一个范例，研究肿瘤发生的表观遗传原因的分子机制。JAK/STAT信号传导的异常激活与许多类型的人类癌症相关，并且JAK中的功能获得性突变已被鉴定为导致人类白血病。JAK/STAT信号传导的作用主要归因于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节。然而，我们最近在果蝇造血肿瘤模型中发现，JAK过度激活会全面破坏异染色质的形成，从而导致不一定是STAT直接靶点的基因去抑制。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，异染色质不稳定形式的全局表观遗传失调可能在癌症的发生和/或进展中起重要作用。我们假设，适当的异染色质形成构成了一种表观遗传肿瘤抑制机制，JAK/STAT信号转导的过度激活部分通过全面破坏异染色质诱导肿瘤形成。为了验证这一假设，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推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认识，也应该为人类癌症治疗带来新的治疗靶点。

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.