Molecular oncology laboratory, S.N. Bose innovation centre, University of Kalyani, Kalyani, West Bengal, 741235, India.
Department of Bioinformatics & Applied Sciences, Indian Institute of Information Technology-, Allahabad, Uttar Pradesh, 211012, India.
Commun Biol. 2022 May 4;5(1):416. doi: 10.1038/s42003-022-03385-x.
The presence of ERG gene fusion; from developing prostatic intraepithelial neoplasia (PIN) lesions to hormone resistant high grade prostate cancer (PCa) dictates disease progression, altered androgen metabolism, proliferation and metastasis. ERG driven transcriptional landscape may provide pro-tumorigenic cues in overcoming various strains like hypoxia, nutrient deprivation, inflammation and oxidative stress. However, insights on the androgen independent regulation and function of ERG during stress are limited. Here, we identify PGC1α as a coactivator of ERG fusion under various metabolic stress. Deacetylase SIRT1 is necessary for PGC1α-ERG interaction and function. We reveal that ERG drives the expression of antioxidant genes; SOD1 and TXN, benefitting PCa growth. We observe increased expression of these antioxidant genes in patients with high ERG expression correlates with poor survival. Inhibition of PGC1α-ERG axis driven transcriptional program results in apoptosis and reduction in PCa xenografts. Here we report a function of ERG under metabolic stress which warrants further studies as a therapeutic target for ERG fusion positive PCa.
ERG 基因融合的存在；从发展中的前列腺上皮内瘤变（PIN）病变到激素抵抗的高级别前列腺癌（PCa），决定了疾病的进展、雄激素代谢的改变、增殖和转移。ERG 驱动的转录景观可能在克服各种压力（如缺氧、营养缺乏、炎症和氧化应激）方面提供促肿瘤发生的线索。然而，关于 ERG 在应激条件下非雄激素依赖性调节和功能的见解有限。在这里，我们确定 PGC1α 是各种代谢应激下 ERG 融合的共激活因子。去乙酰化酶 SIRT1 是 PGC1α-ERG 相互作用和功能所必需的。我们揭示了 ERG 驱动抗氧化基因（SOD1 和 TXN）的表达，有益于 PCa 的生长。我们观察到在高 ERG 表达的患者中这些抗氧化基因的表达增加，与不良预后相关。抑制 PGC1α-ERG 轴驱动的转录程序导致细胞凋亡和减少 PCa 异种移植物。在这里，我们报告了代谢应激下 ERG 的功能，这需要进一步研究作为 ERG 融合阳性 PCa 的治疗靶点。
