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

• 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
• 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

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。