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特征。通过种系缺失或RNAi，Oct1的缺失增强了线粒体功能并拮抗体外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。我们已经确定了一个途径，其中Oct1磷酸化夫妇的压力输入转录输出通过改变目标的选择性。我们的初步研究结果表明，Oct1的缺失会特异性地消耗癌症干细胞群，这是使用两个标准来测量的。我们建议确定Oct1如何调节代谢和“干性”以控制癌症的发生和进展：具体目标1：确定Oct1是否在功能上控制癌症干细胞身份2.2.具体目标2：确定干细胞表型的Oct1活性和靶点 公共卫生相关性：这项工作最令人兴奋的方面是有可能验证Oct1在成人正常和恶性细胞中控制干细胞识别的作用，并确定Oct1转录靶点，这些靶点是观察到的干细胞表型的基础。如果成功的话，这些研究将把Oct1和Oct1调控通路的组成部分放在一类可能适合癌症治疗的靶点中。因此，我们认为，这项建议很有可能推动这一领域的工作。

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.