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: 9794387
• 负责人: Katie L Kathrein
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794387
• 关键词: Affect; Agar; Astrocytoma; Biological Assay; Cell physiology; 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; Proteins; Publications; Regulation; Role; Signal Transduction Pathway; Solid Neoplasm; Stem cells; Testing; Therapeutic; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Zebrafish; base; cancer cell; carcinogenesis; career; combat; genetic inhibitor; inhibitor/antagonist; loss of function; malignant breast neoplasm; neoplastic cell; outcome forecast; screening; small molecule; small molecule inhibitor; stem-like cell; success; targeted treatment; therapy resistant; trait; transcriptome sequencing; transcriptomics; tumor; tumor progression; Affect; Agar; Astrocytoma; Biological Assay; Cell physiology; 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; Proteins; Publications; Regulation; Role; Signal Transduction Pathway; Solid Neoplasm; Stem cells; Testing; Therapeutic; Tissues; Tumor Cell Line; Tumor Suppressor Proteins; Zebrafish; base; cancer cell; carcinogenesis; career; combat; genetic inhibitor; inhibitor/antagonist; loss of function; malignant breast neoplasm; neoplastic cell; outcome forecast; screening; small molecule; small molecule inhibitor; 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-B pathway, implicated in carcinogenesis, tumor progression and drug resistance. We found that Ing4 depletion in zebrafish stimulates NF-B activity and NF-B 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.

抽象的 癌症的多方面性质导致一种复杂且难以治疗的疾病。一个常见 这种疾病的特征是癌细胞重新启动干细胞的能力，如特征，导致异常 基因表达和对治疗的抗性。作为癌症经常异常的分子网络 也是正常干细胞使用的，了解这些途径和机制如何运作至关重要 在干细胞中，由癌细胞利用以促进疾病进展。异常基因表达 肿瘤通常是癌基因表达或抑制肿瘤灭活的结果。肿瘤抑制剂是 特别是靶标的挑战，因为这些蛋白通常缺少或仅在肿瘤中非常低的水平出现 细胞。我们的实验室最近确定了肿瘤抑制剂ING4，染色质修饰剂和转录 含有PhD手指结构域的调节剂，作为造血干细胞规范的关键调节剂。 ING4 已显示在几种类型的人类癌症中被灭活，包括乳房，前列腺，结直肠癌， 卵巢癌和肺癌，星形胶质细胞瘤和肝细胞癌。 ING4表达的丢失是 与预后不良相关，但ING4肿瘤抑制功能的机制尚未完全 理解齿。 ING4的肿瘤抑制活性的潜在机制是通过其负调控 NF-B途径在癌变，肿瘤进展和耐药性中暗示。我们发现4 在 ING4的损失。我们提出的特定目的将使用遗传和药物方法，都在 开发斑马鱼和ING4缺陷的人类肿瘤细胞，以识别打击的潜在机制 癌症中这种蛋白质的丧失。 AIM 1是研究ING4在斑马鱼中灭活对基因的影响 表达并确定丧失后更新的基因表达途径的靶向 将挽救ING4失活对斑马鱼中HSC规范的影响。目标2是确定是否小 NF-κB和其他更新途径的分子抑制剂将挽救ING4损失的影响 斑马鱼的功能。 AIM 3是识别基因和途径，抑制其修复细胞的效应 ING4在哺乳动物肿瘤细胞中灭活，使用斑马鱼和通用的分析结果 在ING4缺陷型人肿瘤细胞中进行的筛查。拟议的研究的成功将是 识别可以补救ING4缺乏症的表型作用的药物的基础，其最终目标是 为ING4灭活的癌症制定治疗策略。