Molecular and Cellular Basis of Oncogene Addiction

癌基因成瘾的分子和细胞基础

• 批准号: 7655214
• 负责人: DEAN W FELSHER
• 金额: $ 32.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655214
• 关键词: Address; Binding; Biological Models; Cancerous; Cell Aging; Cell Line; Cells; Chromatin; Chromatin Structure; DNA Binding; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; Data; Defect; Development; E-Box Elements; Epigenetic Process; Exhibits; Gene Expression; Genes; Genetic; Global Change; Grant; Hematopoietic Neoplasms; Human; Lymphoma; Malignant Neoplasms; Mediating; Molecular; Neoplasms; Oncogene Activation; Oncogenes; Pattern; Phenotype; Physiological; Play; Postdoctoral Fellow; Primary carcinoma of the liver cells; Principal Investigator; Process; Proteins; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Specificity; Stem cells; TP53 gene; Transgenic Model; Tumor-Derived; Tumor-Suppressor Gene Inactivation; Wages; addiction; angiogenesis; anticancer research; base; cancer regression; cancer therapy; cancer type; chromatin modification; effective therapy; genome-wide; graduate student; neoplastic; neoplastic cell; osteosarcoma; overexpression; programs; promoter; receptor; repaired; research study; response; senescence; transcription factor; tumor; tumorigenesis

Cancer is caused by the activation of oncogenes and the inactivation of tumor suppressor genes. The targeted inactivation and repair of these gene products may be a specific and effective therapy for cancer. Previously, we have shown that the inactivation of the MYC oncogene is sufficient to induce sustained regression of hematopoietic tumors [2]. Subsequently, we reported that even brief inactivation of MYC is sufficient to induce sustained tumor regression of osteosarcoma [3, 4]. Our results support the general hypothesis that tumors exhibit the phenomena of oncogene addiction [5, 6]. To explain our findings, we reasoned that MYC inactivation induces a permanent change in the ability of cells to induce a cancer-associated gene expressionprogram. Upon MYC inactivation, there are specific and sustained changes in gene expression [Wu et al, PLoS Genetics [1]; and see Appendix, Shachaf et al, Cancer Research, 2008]. These changes in gene expression are frequently accompanied by permanent changes in the ability of MYC binding to promoter loci, as shown by ChIP. We performed a preliminary ChIP-on-chip analysis for MYC and interrogated changes in binding of other transcription factors in a genome-wide scale. Moreover, we also found that changes in gene expression are associated with specific alterations in chromatin modifications. Importantly, MYC appears to regulate gene expression not just through interactions with the canonical DNA binding sequence (E-Box), but additionally, its binding specificity may be regulated by DNA methylation. We provide new results that illustrate that the TGF-n signaling pathway may play an important role in the mechanism by which MYC inactivation induces changes in gene expression and cellular senescence. Moreover, we provide evidence that MYC regulates DNA methylation. Hence, we hypothesize that MYC inactivation restores auto-regulatory programs, including the induction of CDKIs, through effects on DNA methylation, resulting in the induction of a cellular senescence program. Hence, both cell extrinsic receptor based mechanisms, including TGF-U signaling, as well as cell intrinsic mechanisms, including regulation of DNA methylation, may be critical to oncogene addiction. We now propose experiments and request salary and grant support for a team of 1 principal investigator, 2 post-doctoral fellows and 1 graduate student and a research associates to delineate the role of TGF-13 signaling and DNA methylation on the mechanism of tumor regression upon MYC inactivation. Our results are consistent with the notion that MYC may directly regulate the global chromatin structure; and suggest the surprising idea that MYC-induced tumor cells remain unaware or "amnesic" - as we have recently described [10] - of their cancerous state, yet remain poised to undergo senescence. The results of our proposed experiments will have important implications for the mechanisms by which the MYC oncogene maintains tumorigenesis and the development of new therapies for the treatment of cancer.

癌症是由癌基因的激活和抑癌基因的失活引起的。这些基因产物的靶向失活和修复可能是一种特异而有效的癌症治疗方法。此前，我们已经证明，MYC癌基因的失活足以诱导造血肿瘤的持续消退[2]。随后，我们报道，即使是短暂的MYC失活也足以诱导骨肉瘤的持续肿瘤消退[3，4]。我们的结果支持肿瘤表现出癌基因成瘾现象的普遍假设[5，6]。为了解释我们的发现，我们推断MYC失活会导致细胞诱导癌症相关基因表达程序的能力发生永久性变化。在MYC失活后，基因表达有特定和持续的变化[Wu等人，PLoS Genetics[1]；见附录，Shachaf等人，癌症研究，2008]。如CHIP所示，这些基因表达的变化常常伴随着MYC与启动子位点结合能力的永久性变化。我们对MYC进行了初步的芯片上分析，并询问了全基因组范围内其他转录因子结合的变化。此外，我们还发现，基因表达的变化与染色质修饰的特定变化有关。重要的是，MYC似乎不仅通过与规范DNA结合序列(E-Box)的相互作用来调节基因的表达，而且其结合特异性可能受到DNA甲基化的调节。我们提供的新结果表明，转化生长因子-n信号通路可能在MYC失活诱导基因表达变化和细胞衰老的机制中发挥重要作用。此外，我们还提供了MYC调节DNA甲基化的证据。因此，我们假设MYC失活通过对DNA甲基化的影响恢复了自动调节程序，包括CDKI的诱导，导致了细胞衰老程序的诱导。因此，无论是基于细胞外源受体的机制，包括转化生长因子-U信号，还是细胞内在机制，包括DNA甲基化的调节，都可能是癌基因成瘾的关键。我们现在提议进行实验，并要求为一个由1名首席研究员、2名博士后研究员、1名研究生和1名研究助理组成的团队提供工资和赠款支持，以描述转化生长因子-13信号和DNA甲基化在MYC失活后肿瘤消退机制中的作用。我们的结果与MYC可能直接调节全球染色质结构的概念是一致的，并表明MYC诱导的肿瘤细胞仍然不知道或像我们最近描述的那样“健忘”它们的癌症状态，但仍然准备经历衰老。我们提出的实验结果将对MYC癌基因维持肿瘤形成的机制和癌症治疗新疗法的开发具有重要意义。