Mechanisms of metabolic stress-induced transcriptional regulation in prostate cancer

前列腺癌代谢应激诱导的转录调控机制

基本信息

批准号：
10376802
负责人：
Subhamoy Dasgupta
金额：
$ 35.45万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376802
关键词：
Ablation Accounting Acetylation Aconitate Hydratase Advanced Development Anabolism Androgen Receptor Androgens Automobile Driving Binding Bioenergetics Cancer Patient Carbon Cell Nucleus Citrates Clinical Communication Competence Data Deacetylase Dependence Disease Enzymes Event Fatty Acids Fatty acid glycerol esters GRIP1 gene Genes Genetic Genetic Transcription Glutamine Goals Growth Homing Hormones Human Link Lipids Lysine Malignant neoplasm of prostate Mediating Metabolic Metabolic stress Metabolism Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Mitochondria Modeling Molecular Morbidity - disease rate Mus NCOA2 gene Neoplasm Metastasis Nuclear Nuclear Receptors Oncogenic Organ Organelles Pathogenesis Pathway interactions Patients Physiological Play Primary Lesion Property Prostate Prostatic Neoplasms Proteins Recurrence Refractory Relapse Repression Resistance development Role Signal Transduction Sirtuins Steroid Receptors Therapeutic Transcriptional Activation Transcriptional Regulation Tumor Suppressor Proteins Visceral advanced disease advanced prostate cancer androgen deprivation therapy base bone cancer survival castration resistant prostate cancer enzyme activity fatty acid biosynthesis gene repression gene synthesis genetic corepressor hormone refractory prostate cancer in vivo lipid biosynthesis loss of function men mimetics mitochondrial metabolism mortality mouse model mutant novel programs promoter prostate cancer cell prostate cancer model prostate cancer progression restoration steroid hormone receptor therapy resistant tumor

项目摘要

Metastatic prostate cancer (PCa) remains a major clinical challenge. Although androgen deprivation therapy (ADT) is effective in treating PCa, majority of the patients quickly develop resistance to therapy and the tumor relapses as hormone refractory castration-resistant prostate cancer (CRPC). Men with CRPC frequently progress to an aggressive lethal disease that metastasizes to bones and other visceral organs accounting for high morbidity and mortality. Transcriptional activation of steroid receptor coactivator-2 (SRC-2; also known as NCOA2/TIF2/GRIP1) plays a critical role in the pathogenesis of PCa by driving a metabolic switch towards de novo fatty acid biosynthesis. Although increased lipogenesis is a known hallmark of hormone refractory PCa progression, it is less clear how mitochondrial enzymes communicate with nuclear receptor coregulators to rapidly fuel and support fat biosynthesis. Our preliminary findings indicate that sustained activity of mitochondrial aconitase (ACO2) enzyme is critical for regulating citrate synthesis. We found that acetylation of ACO2 is essential for enzyme functions, which is negatively regulated by sirtuin-3 (SIRT3). In human prostate cancer patients, SIRT3 expression is repressed and increased expression of SRC-2 with concomitant reduction of SIRT3 was found to be a genetic hallmark in metastatic PCa. Based on these findings, we hypothesize that the transcriptional coregulator SRC-2 drives the nuclear-mitochondrial regulatory axis by repressing tumor suppressor SIRT3 thus promoting prostate tumor survival and metastasis competence. So our objectives in this proposal are (1) to investigate the mechanisms regulating sustained activation of mitochondrial ACO2 to promote lipogenesis, (2) define the role of nuclear receptor coregulator SRC-2 regulating SIRT3 expression, and (3) evaluate the impact of this nuclear-mitochondrial regulatory axis on prostate tumor survival and adaptation leading to bone colonization and growth. Our study will uncover molecular links between mitochondrial metabolism and transcriptional regulation that enables hormone refractory PCa adaptation, survival and ultimately metastatic competency.

转移性前列腺癌（PCA）仍然是主要的临床挑战。虽然雄激素剥夺疗法（ADT）有效治疗PCA，大多数患者迅速发展对治疗和肿瘤复发为激素耐火性castration-耐药前列腺癌（CRPC）。经常患有CRPC的男人发展为侵略性致命疾病，该疾病转移到骨骼和其他内脏器官中高发病和死亡率。类固醇受体共激活剂2（SRC-2;也称为 NCOA2/TIF2/GRIP1）通过将代谢开关向DE驱动在PCA的发病机理中起关键作用 Novo脂肪酸生物合成。尽管增加的脂肪形成是激素难治性PCA的已知标志进展，尚不清楚线粒体酶如何与核受体之间的酶进行交流至快速燃料和支持脂肪生物合成。我们的初步发现表明线粒体的持续活动丙酸酶（ACO2）酶对于调节柠檬酸盐合成至关重要。我们发现ACO2的乙酰化为对于酶功能所必需的，该酶功能受SIRTUIN-3（SIRT3）的负调节。在人类前列腺癌中患者，SIRT3表达受到抑制，并增加了SRC-2的表达，并同时减少发现SIRT3是转移性PCA中的遗传标志。根据这些发现，我们假设转录核心节SRC-2通过抑制肿瘤来驱动核线粒体调节轴抑制剂SIRT3因此促进了前列腺肿瘤的存活和转移能力。所以我们的目标建议是（1）研究调节线粒体ACO2持续激活以促进的机制脂肪生成，（2）定义了调节SIRT3表达的核受体组合剂SRC-2的作用，（3）评估该核线粒体调节轴对前列腺肿瘤存活和适应的影响导致骨定殖和生长。我们的研究将发现线粒体之间的分子联系代谢和转录调节，可激发激素难治性PCA适应，生存和最终的转移能力。