Gene regulation of Oct1: implications of metabolism, stemness and cancer

Oct1 的基因调控：代谢、干性和癌症的影响

• 批准号: 7881146
• 负责人: DEAN TANTIN
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881146
• 关键词: A549; Adult; BRCA1 gene; Cancer Control; Categories; Cell physiology; Cells; Complex; Couples; Doxorubicin; Fibroblasts; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Glycolysis; Human; Hydrogen Peroxide; In Vitro; Ionizing radiation; MCF7 cell; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Mitochondria; Mus; Output; POU2F1 gene; Pathway interactions; Phenotype; Phosphorylation; Population; Proteins; RNA Interference; Radio; Resistance; Role; Side; Signal Transduction; Site; Stem cells; Stress; Testing; Tumor Cell Line; Tumor Stem Cells; Tumorigenicity; Work; Xenograft Model; aldehyde dehydrogenase 1; cancer cell; cancer stem cell; cancer therapy; in vivo; neoplastic cell; public health relevance; stem cell population; stemness; transcription factor; tumor growth

DESCRIPTION (provided by applicant): The Oct1 (POU2F1) transcription factor is a potent regulator of metabolism and tumorigenicity. Oct1 promotes glycolysis at the expense of mitochondrial metabolism, a metabolic profile indicative of stem cells and tumor cells. Loss of Oct1, either by germline deletion or RNAi, augments mitochondrial function and antagonizes transformation in vitro and tumor growth in vivo. Loss of Oct1 also sensitizes cells to ionizing radiation (IR), H2O2 and doxorubicin. Our new findings show that Oct1 is highly expressed in stem cells, which tend to be chemo- and radio-resistant. We have identified a pathway in which Oct1 phosphorylation couples stress inputs to transcriptional output through altered target selectivity. Our preliminary findings show that loss of Oct1 specifically depletes cancer stem cell populations as measured using two criteria. We propose to identify how Oct1 regulates metabolism and "stemness" to control cancer onset and progression: 2.1. Specific Aim 1: Determine whether Oct1 functionally controls cancer stem cell identity 2.2. Specific Aim 2: Identify Oct1 activities and targets underlying the stem cell phenotype PUBLIC HEALTH RELEVANCE: The most exiting aspects of this work are the potential to verify a role for Oct1 in the control of stem cell identify in adult normal and malignant cells and to identify Oct1 transcription targets that underlie the observed stem cell phenotypes. If successful, these studies will place Oct1 and components of Oct1-regulated pathways in a category of targets that may be suitable for cancer therapies. Therefore, we feel that this proposal has a strong possibility of moving the field forward.

描述（由申请人提供）：OCT1（POU2F1）转录因子是代谢和肿瘤性的有效调节剂。 OCT1以线粒体代谢为代价促进糖酵解，该代谢是一种代表干细胞和肿瘤细胞的代谢特征。通过种系缺失或RNAi的OCT1丧失，可以增强线粒体功能，并在体内拮抗体外转化和肿瘤生长。 OCT1的丧失还使细胞对电离辐射（IR），H2O2和阿霉素的敏感性敏感。我们的新发现表明，OCT1在干细胞中高度表达，这些干细胞倾向于化学和放射性。我们已经确定了一个途径，其中OCT1磷酸化伴侣通过改变目标选择性将压力输入到转录输出。我们的初步发现表明，OCT1的丧失特异性耗尽了使用两个标准测量的癌症干细胞群体。我们建议确定OCT1如何调节新陈代谢和“ Stemness”来控制癌症的发作和进展：2.1。特定目标1：确定OCT1是否在功能上控制癌症干细胞身份2.2。特定目标2：确定干细胞表型的OCT1活动和目标 公共卫生相关性：这项工作最退出的方面是验证OCT1在控制成人正常和恶性细胞中识别干细胞中的作用，并确定构成观察到的干细胞表型的基于的OCT1转录靶标。如果成功，这些研究将将OCT1和OCT1调节途径的组成部分置于可能适合癌症疗法的靶标。因此，我们认为该提议有很大的可能性可以向前推进该领域。