Mechanisms of metabolic stress-induced transcriptional regulation in prostate cancer

转移性前列腺癌(PCa)仍然是临床上的一大挑战。虽然雄激素剥夺疗法 (ADT)治疗前列腺癌有效，大多数患者很快就会对治疗和肿瘤产生抵抗力 复发为激素难治性去势抵抗前列腺癌(CRPC)。男性常见的慢性前列腺癌 一种侵袭性致命疾病的进展，这种疾病转移到骨骼和其他内脏器官，占 高发病率和高死亡率。类固醇受体共激活因子-2(SRC-2；也称为 NCOA2/TIF2/GRIP1)在前列腺癌的发病机制中起重要作用 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已知标志 进展，目前尚不清楚线粒体酶如何与核受体协同调节因子进行沟通 快速补充和支持脂肪的生物合成。我们的初步发现表明，线粒体的持续活动 乌头酸酶(ACO2)是调节柠檬酸合成的关键酶。我们发现ACO2的乙酰化是 SIRT3对酶的功能是必不可少的，而SIRT3对SIRT3负调控。在人类前列腺癌中 SIRT3的表达被抑制，SRC-2的表达增加，伴随着 SIRT3被发现是转移性前列腺癌的一个遗传标志。根据这些发现，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 抑制子SIRT3从而促进前列腺癌的存活和转移能力。所以我们的目标是 建议如下：(1)探讨线粒体ACO2持续激活的调控机制 脂肪生成，(2)确定核受体辅助调节因子SRC-2调节SIRT3表达的作用，以及(3) 评估核-线粒体调节轴对前列腺癌生存和适应的影响 导致骨骼定植和生长。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、存活和 最终的转移性能力。

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.