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.

项目概要 迫切需要开发新的致癌治疗选择。此举的目标 该提案旨在通过对驱动分子途径的新认识来帮助满足这一需求 肿瘤发生。最近发表的数据揭示了热休克因子 1 的促癌活性 (HSF1)，热休克反应的主要调节因子，并表明 AMP 激活蛋白 激酶 (AMPK) 磷酸化 HSF1 的 S121，使其失活，从而破坏恶性肿瘤。 HSF1 是否会相互影响 AMPK 尚待探索。初步数据表明 HSF1 与 AMPK 发生物理相互作用并抑制 AMPK，与 HSF1 转录活性无关 处于稳定状态。 HSF1 的基因缺失会抑制细胞脂肪生成、胆固醇合成、 蛋白质胆固醇化（对于目标蛋白质的稳定性和活性很重要）和脂肪量 通过 AMPK 在混合背景小鼠中进行实验。 HSF1的过度表达促进脂肪生成 表型和肿瘤生长。这些结果表明 HSF1 独立转录 抑制 AMPK 促进肿瘤生长的脂肪生成表型。拟建项目地址 通过追求两个具体目标来实现这一假设。目标1：阐明详细机制 HSF1 介导的 AMPK 抑制。首先，将使用 HSF1 肽的高分辨率文库 研究体外和体内模型中的 AMPK 抑制。其次，将使用生物物理方法 确定 HSF1 对 AMPK 构象的影响。目标 2：检验 HSF1 的假设 支持肿瘤生长中的脂质生物合成。一、HSF1到底是如何调控AMPK介导的 将测定脂肪生成、胆固醇合成和蛋白质胆固醇化。其次， 将在 AMPK 抑制的近交小鼠中研究其机制。三、转录 HSF1 的独立活性及其相关的 AMPK 调节的脂质和胆固醇代谢 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 提供对肿瘤进展中蛋白质稳态的更深入了解，研究一种新的 癌症治疗的治疗靶点，并确定可提供信息的基因表达特征 临床进展和结果。该项目在概念和技术上都具有创新性，因为它将： i) 检查 HSF1 作为 AMPK 新型抑制剂的作用，ii) 研究蛋白质胆固醇化 由 HSF1 和 AMPK 开发，以及 iii) 开发内源性 HSF1 作为癌症的新型预后指标 患者生存。该提案将提供一个踏脚石，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， 为突破性发现做出贡献，从而改善治疗策略。