美国加州大学洛杉矶分校Andrew S. Goldstein团队发现，前列腺谱系特异性代谢影响管腔分化和对抗雄激素治疗的反应。2023年12月4日，国际知名学术期刊《自然—细胞生物学》杂志在线发表了这一成果。

研究人员表示，谱系转换是前列腺发育、肿瘤发生和耐药性的一个核心特征。众所周知，表观遗传学的变化会驱动前列腺细胞谱系的转换，但上游代谢信号如何促进前列腺上皮细胞身份的调控仍不清楚。

为了填补这一空白，研究人员开发了一种对原代前列腺上皮细胞进行代谢组学研究的方法。利用这种方法，研究人员发现前列腺的基底细胞和管腔细胞表现出不同的代谢组和营养利用模式。此外，从基底细胞到管腔细胞的分化伴随着丙酮酸氧化的增加。研究人员确定线粒体丙酮酸载体和随后的乳酸积累是前列腺腔内特性的调节因子。抑制线粒体丙酮酸载体或补充外源性乳酸会导致大规模染色质重塑，从而影响谱系特异性转录因子以及对抗雄激素治疗的反应。这些结果确立了新陈代谢和前列腺上皮细胞系特征的相互调控。

附：英文原文

Title: Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment

Author: Giafaglione, Jenna M., Crowell, Preston D., Delcourt, Amelie M. L., Hashimoto, Takao, Ha, Sung Min, Atmakuri, Aishwarya, Nunley, Nicholas M., Dang, Rachel M. A., Tian, Mao, Diaz, Johnny A., Tika, Elisavet, Payne, Marie C., Burkhart, Deborah L., Li, Dapei, Navone, Nora M., Corey, Eva, Nelson, Peter S., Lin, Neil Y. C., Blanpain, Cedric, Ellis, Leigh, Boutros, Paul C., Goldstein, Andrew S.

Issue&Volume: 2023-12-04

Abstract: Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

DOI: 10.1038/s41556-023-01274-x

Source: https://www.nature.com/articles/s41556-023-01274-x