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:
  • 金额:
    $ 34.99万
  • 依托单位:
  • 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

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)仍然是一个主要的临床挑战。虽然雄激素剥夺疗法 (ADT)虽然这种药物治疗前列腺癌是有效的,但大多数患者很快就会对治疗产生耐药性, 复发为激素难治性去势抵抗性前列腺癌(CRPC)。CRPC患者经常 发展为侵袭性致命疾病,转移到骨骼和其他内脏器官, 发病率和死亡率高。类固醇受体共激活因子-2(SRC-2;也称为 NCOA 2/TIF 2/GRIP 1)通过驱动代谢开关向前列腺癌的发展,在前列腺癌的发病机制中起着关键作用。 新脂肪酸生物合成。虽然脂肪生成增加是激素难治性前列腺癌的一个已知标志, 随着研究的进展,线粒体酶如何与核受体辅助调节因子沟通, 快速燃料和支持脂肪生物合成。我们的初步研究结果表明, 乌头酸酶(aconitase,ACO 2)是调节柠檬酸合成的关键酶。我们发现,乙酰化的ACO 2是 对酶功能至关重要,其由sirtuin-3(SIRT 3)负调控。在人前列腺癌 患者中,SIRT 3表达被抑制,SRC-2表达增加,伴随着SIRT 3表达的减少。 发现SIRT 3是转移性PCa的遗传标志。基于这些发现,我们假设 转录辅助调节因子SRC-2通过抑制肿瘤来驱动核-线粒体调节轴 抑制SIRT 3,从而促进前列腺肿瘤存活和转移能力。所以我们的目标是 我们的建议是:(1)研究线粒体ACO 2持续激活的机制, 脂肪生成,(2)确定核受体辅助调节剂SRC-2调节SIRT 3表达的作用,和(3) 评估核-线粒体调节轴对前列腺肿瘤生存和适应的影响 导致骨定植和生长。我们的研究将揭示线粒体与 代谢和转录调控,使激素难治性PCa适应,生存和 最终转移能力。

项目成果

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Subhamoy Dasgupta其他文献

Subhamoy Dasgupta的其他文献

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{{ truncateString('Subhamoy Dasgupta', 18)}}的其他基金

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
  • 财政年份:
    2023
  • 资助金额:
    $ 34.99万
  • 项目类别:
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:
    10376802
  • 财政年份:
    2021
  • 资助金额:
    $ 34.99万
  • 项目类别:
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:
    10209389
  • 财政年份:
    2021
  • 资助金额:
    $ 34.99万
  • 项目类别:
Decoding the nuclear metabolic processes regulating gene transcription
解码调节基因转录的核代谢过程
  • 批准号:
    10001134
  • 财政年份:
    2020
  • 资助金额:
    $ 34.99万
  • 项目类别:
INVESTIGATING THE ROLE OF THE TRANSCRIPTIONAL COREGULATOR SRC-2 IN CASTRATION RESISTANT PROSTATE CANCER
研究转录核心调节子 SRC-2 在去势抵抗性前列腺癌中的作用
  • 批准号:
    9763341
  • 财政年份:
    2017
  • 资助金额:
    $ 34.99万
  • 项目类别:

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