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

描述（由申请人提供）：Oct1 （POU2F1）转录因子是代谢和致瘤性的有效调节因子。Oct1以线粒体代谢为代价促进糖酵解，线粒体代谢是干细胞和肿瘤细胞的代谢谱。无论是通过种系缺失还是RNAi， Oct1的缺失都会增强线粒体功能，并在体外对抗转化和体内肿瘤生长。Oct1的缺失也使细胞对电离辐射（IR）、H2O2和阿霉素敏感。我们的新发现表明，Oct1在干细胞中高度表达，而干细胞往往具有化疗和放射抗性。我们已经确定了一种途径，其中Oct1磷酸化通过改变靶标选择性将应激输入偶联到转录输出。我们的初步研究结果表明，使用两个标准测量Oct1的缺失会特异性地消耗癌症干细胞群。我们建议确定Oct1如何调节代谢和“干性”来控制癌症的发生和进展。特异性目的1：确定Oct1是否在功能上控制癌症干细胞的身份特异性目标2：确定Oct1活性和干细胞表型的靶标

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.