Schaub-Clerigué Ariane, Hermanova Ivana, Pintor-Rial Ainara, Sydorenko Mariia, Valcarcel-Jimenez Lorea, Macchia Alice, Lectez Benoit, Garcia-Longarte Saioa, Fagoaga-Eugui Maider, Astobiza Ianire, Martín-Martín Natalia, Zabala-Letona Amaia, Pujana-Vaquerizo Mikel, Royo Félix, Azkargorta Mikel, Berra Edurne, Sutherland James D, Peinado Héctor, Falcón-Perez Juan Manuel, Elortza Félix, Carracedo Arkaitz, Torrano Verónica
Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Leioa, Spain.
Cancer Cell Signaling and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain.
Cell Death Dis. 2025 Apr 23;16(1):330. doi: 10.1038/s41419-025-07639-4.
Prostate cancer is the fifth cause of death by cancer worldwide, second in incidence in the male population. The definition of the molecular basis of its development and the oncogenic signals driving lethality continue to be important objectives in prostate cancer research. Prior work from others and us has demonstrated that loss of PGC1α expression results in a metabolic, signaling and transcriptional reprogramming that supports the development of metastatic disease. However, we do not fully understand the spectrum of tumor suppressive effects regulated by this co-regulator. Here we show that PGC1α governs non-cell autonomous paracrine tumor suppression in prostate cancer. A systematic analysis of the transcriptional landscapes associated to PGC1α loss of expression revealed that PGC1α alters the expression of genes encoding for secreted proteins. Cell secretome studies corroborated that PGC1α-dependent ERRα regulation in prostate cancer cells suppresses the growth of tumor cells exposed to their conditioned media, independently of androgen receptor status. The integration of in vitro and in vivo secretomics data and genetic perturbation assays revealed spermidine synthase as a transcriptional target of PGC1α and mediator of the paracrine metabolic growth suppressive effect. Moreover, the activity of the regulatory axis PGC1α-ERRα-SRM was reflected in patients and had prognostic value. Altogether, this work provides unprecedented evidence of the non-cell autonomous suppressive role of PGC1α, which broadens the view of this co-regulator as a multifactorial tumor suppressor in prostate cancer.
前列腺癌是全球第五大致死性癌症，在男性群体中的发病率位居第二。其发展的分子基础定义以及驱动致死性的致癌信号仍是前列腺癌研究的重要目标。此前他人及我们的研究工作已表明，PGC1α表达缺失会导致代谢、信号传导及转录重编程，从而支持转移性疾病的发展。然而，我们尚未完全了解这种共调节因子所调控的肿瘤抑制效应的范围。在此，我们表明PGC1α在前列腺癌中发挥非细胞自主性旁分泌肿瘤抑制作用。对与PGC1α表达缺失相关的转录图谱进行系统分析发现，PGC1α会改变编码分泌蛋白的基因的表达。细胞分泌组研究证实，前列腺癌细胞中PGC1α依赖性ERRα调节可抑制暴露于其条件培养基中的肿瘤细胞生长，且与雄激素受体状态无关。体外和体内分泌组学数据与基因扰动试验相结合，揭示精胺合酶是PGC1α的转录靶点以及旁分泌代谢生长抑制效应的介导因子。此外，PGC1α - ERRα - SRM调节轴的活性在患者中有所体现并具有预后价值。总之，这项工作提供了前所未有的证据，证明PGC1α具有非细胞自主性抑制作用，这拓宽了人们对这种共调节因子作为前列腺癌中多因素肿瘤抑制因子的认识。
