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：
10590678
负责人：
Subhamoy Dasgupta
金额：
$ 34.99万
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/10590678
关键词：
Ablation Accounting Acetylation Aconitate Hydratase Advanced Development Anabolism Androgen Receptor Androgens Automobile Driving Binding Bioenergetics Cancer Patient Carbon Castration 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 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 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）仍然是一个重大的临床挑战。尽管雄激素剥夺疗法 (ADT) 治疗 PCa 有效，大多数患者很快对治疗和肿瘤产生耐药性复发为激素难治性去势抵抗性前列腺癌（CRPC）。男性经常患有 CRPC 进展为一种侵袭性致命疾病，转移至骨骼和其他内脏器官发病率和死亡率高。类固醇受体辅激活因子-2（SRC-2；也称为 NCOA2/TIF2/GRIP1) 通过驱动代谢转变，在 PCa 的发病机制中发挥着关键作用。新脂肪酸生物合成。尽管脂肪生成增加是激素难治性前列腺癌的一个已知标志随着进展的进展，目前还不清楚线粒体酶如何与核受体共调节因子进行通信快速提供燃料并支持脂肪生物合成。我们的初步研究结果表明线粒体的持续活性乌头酸酶 (ACO2) 对于调节柠檬酸合成至关重要。我们发现ACO2的乙酰化是对酶功能至关重要，它受到 Sirtuin-3 (SIRT3) 的负调控。在人类前列腺癌中在患者中，SIRT3 表达受到抑制，SRC-2 表达增加，同时 SRC-2 表达减少 SIRT3 被发现是转移性 PCa 的遗传标志。基于这些发现，我们假设转录共调节因子SRC-2通过抑制肿瘤来驱动核线粒体调节轴 SIRT3 抑制剂从而促进前列腺肿瘤的存活和转移能力。所以我们的目标是建议是（1）研究调节线粒体ACO2持续激活的机制，以促进脂肪生成，(2) 定义核受体辅助调节因子 SRC-2 调节 SIRT3 表达的作用，以及 (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植和生长。我们的研究将揭示线粒体之间的分子联系代谢和转录调节，使激素难治性 PCa 适应、生存和最终的转移能力。