A transcription-independent role of HSF1 in tumorigenesis via suppression of AMPK

HSF1 通过抑制 AMPK 在肿瘤发生中发挥非转录依赖性作用

• 批准号: 10436139
• 负责人: Kuo-Hui Su
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436139
• 关键词: 5' -AMP-activated protein kinase; Address; Automobile Driving; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Cancer Cell Growth; Cancer Patient; Cell Survival; Cell model; Cells; Cholesterol; Cholesterol Homeostasis; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Fatty Acids; Fatty acid glycerol esters; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Heat-Shock Response; Homeostasis; Human; Impairment; In Vitro; Inbred Mouse; Investigation; Lead; Libraries; Light; Link; Lipids; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Metabolic Activation; Molecular; Molecular Conformation; Mus; Oncogenic; Outcome; Pathway interactions; Peptide Library; Peptides; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Process; Production; Protein Biosynthesis; Protein Kinase; Protein phosphatase; Proteins; Proteome; Proteomics; Publishing; Recombinant Proteins; Regulation; Reporting; Research; Resolution; Role; SHH gene; STK11 gene; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Proteins; Work; Xenograft Model; base; biological adaptation to stress; biophysical techniques; cancer diagnosis; cancer therapy; carcinogenesis; career; cell growth; cholesterol biosynthesis; heat-shock factor 1; improved; in vivo; in vivo Model; inhibitor; innovation; lipid biosynthesis; lipid metabolism; melanoma; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutics; overexpression; prognostic indicator; proteostasis; proteotoxicity; rational design; sensor; small molecule inhibitor; smoothened signaling pathway; stressor; targeted cancer therapy; transcription factor; treatment strategy; tumor; tumor growth; tumor progression; tumorigenesis

Project Summary There is an urgent need to develop new therapeutic options for carcinogenesis. The goal of this proposal is to help fulfill this need by shedding new light on the molecular pathways driving tumorigenesis. Recently published data reveals pro-oncogenic activity of heat shock factor 1 (HSF1), the master regulator of the heat shock response, and indicate that AMP-activated protein kinase (AMPK) phosphorylates S121 of HSF1, inactivating it and thereby disrupting malignancy. Whether HSF1 reciprocally impacts AMPK has yet to be explored. Preliminary data indicate that HSF1 physically interacts with and inhibits AMPK independently of HSF1 transcriptional activity at steady state. Genetic deletion of HSF1 suppresses cellular lipogenesis, cholesterol synthesis, protein cholesteroylation (important for the stability and activity of the target protein), and fat mass in mixed background mice through AMPK. Overexpression of HSF1 promotes a lipogenic phenotype and tumor growth. These results suggest that HSF1 transcriptionally independently inhibits AMPK to promote lipogenic phenotype of tumor growth. The proposed project addresses this hypothesis by pursuing two Specific Aims. Aim 1: To elucidate the detailed mechanism of HSF1-mediated AMPK suppression. First, a high-resolution library of HSF1 peptides will be used to study AMPK inhibition in in vitro and in vivo models. Second, a biophysical method will be used to determine the impact of HSF1 on AMPK conformation. Aim 2: To test the hypothesis that HSF1 supports lipid biosynthesis in tumor growth. First, how exactly HSF1 regulates AMPK-mediated lipogenesis, cholesterol synthesis, and protein cholesteroylation will be determined. Second, the mechanism will be studied in inbred mice with AMPK suppression. Third, the transcriptionally independent activity of HSF1 and its associated AMPK-regulated lipid and cholesterol metabolism will be studied in a human melanoma xenograft model. This proposal is significant because it will provide a deeper understanding of proteostasis in tumor progression, investigate a novel therapeutic target for cancer treatment, and identify a gene expression signature that informs clinical progression and outcomes. The project is conceptually and technically innovative as it will: i) examine the role of HSF1 as a novel inhibitor for AMPK, ii) investigate protein cholesteroylation by HSF1 and AMPK, and iii) develop endogenous HSF1 as a novel prognostic indicator for cancer patient survival. The proposal will provide a stepping stone to enable the candidate to establish an independent research career and ultimately become a leader in the field of carcinogenesis, contributing to breakthrough discoveries that lead to improved treatment strategies.

项目摘要 目前迫切需要开发新的致癌治疗方案。这样做的目的是 一项提议是通过揭示分子驱动的新途径来帮助满足这一需求 肿瘤发生学。最近公布的数据显示热休克因子1的促肿瘤活性 热休克反应的主要调节因子(HSF1)，表明AMP激活的蛋白 激酶(AMPK)使HSF1的S121磷酸化，使其失活，从而破坏肿瘤的发生。 HSF1是否会相互影响AMPK尚不清楚。初步数据显示， HSF1与AMPK相互作用并独立于HSF1转录活性抑制AMPK 处于稳定状态。HSF1基因缺失抑制细胞脂肪生成，胆固醇合成， 蛋白质胆固醇基化(对目标蛋白质的稳定性和活性很重要)，以及脂肪质量 在混合背景小鼠中通过AMPK。HSF1的过表达促进脂肪生成 表型与肿瘤生长的关系。这些结果表明，HSF1在转录上是独立的 抑制AMPK促进肿瘤生长的造脂表型。拟议的项目涉及 这一假设通过追求两个具体目标来实现。目的1：阐明心力衰竭的具体机制。 HSF1介导的AMPK抑制。首先，将使用HSF1多肽的高分辨率文库 研究AMPK的体外和体内抑制作用。第二，将使用生物物理方法 确定HSF1对AMPK构象的影响。目的2：检验HSF1的假设 支持肿瘤生长过程中的脂质生物合成。首先，HSF1到底是如何调控AMPK介导的 将确定脂肪生成、胆固醇合成和蛋白质胆固醇酰化。第二， 将在近交系小鼠身上研究抑制AMPK的机制。第三，在转录上 HSF1及其相关的AMPK调节脂质和胆固醇代谢的独立活性 将在人类黑色素瘤异种移植模型中进行研究。这项提议意义重大，因为它将 提供对蛋白质平衡在肿瘤进展中的更深层次的理解，研究一种新的 癌症治疗的治疗靶点，并确定一个基因表达标志，以告知 临床进展和结果。该项目在概念和技术上都是创新的，因为它将： I)研究HSF1作为一种新的AMPK抑制剂的作用，ii)研究蛋白质胆固醇酰化 通过HSF1和AMPK，以及iii)发展内源性HSF1作为癌症预后的新指标 病人存活率。该提案将提供一个垫脚石，使候选人能够建立 独立的研究生涯，并最终成为致癌领域的领导者， 有助于突破性发现，从而改进治疗策略。