Remediating Ing4 tumor suppressor deficiency using a zebrafish model

使用斑马鱼模型修复 Ing4 肿瘤抑制因子缺陷

• 批准号: 10403538
• 负责人: Katie L Kathrein
• 金额: $ 1.24万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2023-12-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403538
• 关键词: Affect; Agar; Astrocytoma; Biological Assay; Characteristics; Chromatin Remodeling Factor; Colorectal Cancer; Developmental Cell Biology; Disease; Disease Progression; Drug resistance; Embryo; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Goals; Grant; Growth; Hematologic Neoplasms; Hematopoietic Stem Cell Specification; Hematopoietic stem cells; Human; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mammalian Cell; Modeling; Molecular; Nature; Oncogenes; PHD Finger; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Play; Primary carcinoma of the liver cells; Prognosis; Proteins; Publications; Regulation; Role; Signal Transduction Pathway; Solid Neoplasm; Testing; Therapeutic; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Zebrafish; base; cancer cell; carcinogenesis; career; genetic inhibitor; inhibitor; loss of function; malignant breast neoplasm; neoplastic cell; screening; small molecule; small molecule inhibitor; stem cell function; stem cells; stem-like cell; success; targeted treatment; therapy resistant; trait; transcriptome sequencing; transcriptomics; tumor; tumor progression

ABSTRACT The multifaceted nature of cancer results in a disease that is complicated and difficult to treat. One common characteristic of this disease is the ability of cancer cells to re-acquire stem-cell like traits resulting in aberrant gene expression and resistance to therapy. As the molecular networks that are frequently aberrant in cancer are also utilized by normal stem cells, it is critical to understand how these pathways and mechanisms function in stem cells and are harnessed by cancer cells to promote disease progression. Aberrant gene expression in tumors is often a result of oncogene expression or tumor suppressor inactivation. Tumor suppressors are particularly challenging to target as these proteins are often missing or present only at very low levels in tumor cells. Our lab has recently identified the tumor suppressor, ING4, a chromatin modifier and a transcriptional regulator containing a PHD finger domain, as a critical regulator of hematopoietic stem cell specification. ING4 has been shown to be inactivated in several types of human cancer, including breast, prostate, colorectal, ovarian and lung cancers, astrocytomas, and hepatocellular carcinomas. Loss of ING4 expression is associated with a poor prognosis but the mechanisms of tumor-suppressive functions of ING4 are not yet fully understood. A potential mechanism of tumor suppressor activity of ING4 is through its negative regulation of the NF-κB pathway, implicated in carcinogenesis, tumor progression and drug resistance. We found that Ing4 depletion in zebrafish stimulates NF-κB activity and NF-κB inhibition can rescue HSC deficiency caused by the loss of Ing4. Our proposed Specific Aims will use both genetic and pharmacological approaches, both in developing zebrafish and in ING4-deficient human tumor cells, to identify potential mechanisms for combating the loss of this protein in cancer. Aim 1 is to investigate the effects of Ing4 inactivation in zebrafish on gene expression and to determine if targeting of gene expression pathways that are upregulated upon loss of Ing4 would rescue the effects of Ing4 inactivation on HSC specification in zebrafish. Aim 2 is to determine if small molecule inhibitors of the NF-κB and other upregulated pathways would rescue the effects of Ing4 loss of function in zebrafish. Aim 3 is to identify genes and pathways, inhibition of which remediates cellular effects of ING4 inactivation in mammalian tumor cells, by using the results of the analysis in zebrafish and of a genetic screen conducted in ING4-deficient human tumor cells. The success of the proposed study will serve as the basis for identifying drugs that could remediate phenotypic effects of the ING4 deficiency, with the ultimate goal of developing therapeutic strategies for cancers where ING4 has been inactivated.

摘要 癌症的多面性导致疾病复杂且难以治疗。 这种疾病的特征是癌细胞重新获得干细胞样特征的能力，从而导致异常的细胞增殖。 基因表达和对治疗的抗性。作为在癌症中经常异常的分子网络， 也被正常干细胞利用，因此了解这些途径和机制如何发挥作用至关重要。 并被癌细胞利用来促进疾病进展。基因表达异常 肿瘤通常是癌基因表达或肿瘤抑制因子失活的结果。肿瘤抑制剂是 由于这些蛋白质在肿瘤中通常缺失或仅以非常低的水平存在， 细胞我们的实验室最近发现了肿瘤抑制因子ING 4，一种染色质修饰剂和一种转录因子。 作为造血干细胞特化的关键调节剂，含有PHD指结构域的调节剂。ING4 已经显示在几种类型的人类癌症中失活，包括乳腺癌，前列腺癌，结肠直肠癌， 卵巢癌和肺癌、星形细胞瘤和肝细胞癌。ING 4表达的缺失是 与预后不良相关，但ING 4的抑瘤作用机制尚不完全 明白ING 4的肿瘤抑制活性的一个潜在机制是通过其负调节 NF-κB通路，与癌发生、肿瘤进展和耐药性有关。我们发现Ing 4 在斑马鱼中的缺失刺激NF-κB活性，并且NF-κB抑制可以挽救由 失去Ing 4。我们提出的具体目标将使用遗传和药理学方法， 开发斑马鱼和ING 4缺陷的人类肿瘤细胞，以确定潜在的机制， 这种蛋白质在癌症中的丢失。目的1：研究斑马鱼Ing 4基因失活对基因表达的影响。 以确定是否靶向在Ing 4缺失时上调的基因表达途径， 将挽救Ing 4失活对斑马鱼中HSC特化的影响。目标2是确定是否小 NF-κB和其他上调途径的分子抑制剂将挽救Ing 4丢失的作用， 在斑马鱼中的作用目的3是鉴定基因和途径，抑制这些基因和途径可以补救细胞毒性效应。 哺乳动物肿瘤细胞中的ING 4失活，通过使用在斑马鱼中的分析结果和一种遗传分析方法， 在ING 4缺陷的人肿瘤细胞中进行的筛选。拟议研究的成功将作为 确定可以补救ING 4缺乏的表型效应的药物的基础，最终目标是 开发治疗ING 4失活癌症的策略。