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: 10818087
• 负责人: Subhamoy Dasgupta
• 金额: $ 5.26万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818087
• 关键词: Accounting; Acetylation; Aconitate Hydratase; Anabolism; Automobile Driving; Cancer Patient; Citrates; Clinical; Communication; Competence; Disease; Enzymes; Fatty acid glycerol esters; GRIP1 gene; Genetic; Genetic Transcription; Goals; Growth; Hormones; Human; Link; Malignant neoplasm of prostate; Metabolic; Metabolic stress; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Mitochondria; Molecular; Morbidity - disease rate; NCOA2 gene; Neoplasm Metastasis; Nuclear; Nuclear Receptors; Organ; Pathogenesis; Patients; Play; Prostatic Neoplasms; Refractory; Repression; Resistance development; Role; Sirtuins; Steroid Receptors; Transcriptional Activation; Transcriptional Regulation; Tumor Suppressor Proteins; Visceral; androgen deprivation therapy; bone; castration resistant prostate cancer; fatty acid biosynthesis; hormone refractory prostate cancer; lipid biosynthesis; men; mitochondrial metabolism; mortality; prostate cancer cell; prostate cancer progression; 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）仍然是一个主要的临床挑战。虽然雄激素剥夺疗法