Abstract：
Metabolic reprogramming is considered as a hallmark of cancer and is clinically exploited as a novel target for therapy. The E2F transcription factor-1 (E2F1) regulates various cellular processes, including proliferative and metabolic pathways, and acts, depending on the cellular and molecular context, as an oncogene or tumor suppressor. The latter is evident by the observation that E2f1-knockout mice develop spontaneous tumors, including uterine sarcomas. This dual role warrants a detailed investigation of how E2F1 loss impacts metabolic pathways related to cancer progression. Our data indicate that E2F1 binds to the promoter of several glutamine metabolism-related genes. Interestingly, the expression of genes in the glutamine metabolic pathway were increased in mouse embryonic fibroblasts (MEFs) lacking E2F1. In addition, we confirm that E2f1-/- MEFs are more efficient in metabolizing glutamine and producing glutamine-derived precursors for proliferation. Mechanistically, we observe a co-occupancy of E2F1 and MYC on glutamine metabolic promoters, increased MYC binding after E2F1 depletion and that silencing of MYC decreased the expression of glutamine-related genes in E2f1-/- MEFs. Analyses of transcriptomic profiles in 29 different human cancers identified uterine sarcoma that showed a negative correlation between E2F1 and glutamine metabolic genes. CRISPR/Cas9 knockout of E2F1 in the uterine sarcoma cell line SK-UT-1 confirmed elevated glutamine metabolic gene expression, increased proliferation and increased MYC binding to glutamine-related promoters upon E2F1 loss. Together, our data suggest a crucial role of E2F1 in energy metabolism and metabolic adaptation in uterine sarcoma cells.
摘要：
代谢重编程被认为是癌症的标志，并在临床上被用作治疗的新靶标。E2F转录因子-1（E2F1）调节各种细胞过程，包括增殖和代谢途径，和行为，取决于细胞和分子环境，作为癌基因或肿瘤抑制因子。观察到E2f1基因敲除小鼠发生自发性肿瘤，包括子宫肉瘤.这种双重作用需要详细研究E2F1损失如何影响与癌症进展相关的代谢途径。我们的数据表明E2F1与几个谷氨酰胺代谢相关基因的启动子结合。有趣的是,缺乏E2F1的小鼠胚胎成纤维细胞（MEFs）中谷氨酰胺代谢途径中的基因表达增加。此外,我们证实E2f1-/-MEFs在代谢谷氨酰胺和产生谷氨酰胺衍生的增殖前体方面更有效。机械上,我们观察到E2F1和MYC在谷氨酰胺代谢启动子上的共同占据，E2F1耗尽后MYC结合增加，MYC沉默降低了E2f1-/-MEF中谷氨酰胺相关基因的表达。对29种不同人类癌症的转录组学分析发现，子宫肉瘤显示E2F1和谷氨酰胺代谢基因之间呈负相关。子宫肉瘤细胞系SK-UT-1中E2F1的CRISPR/Cas9敲除证实谷氨酰胺代谢基因表达升高，E2F1丢失后，增殖增加，MYC与谷氨酰胺相关启动子的结合增加。一起,我们的数据表明E2F1在子宫肉瘤细胞的能量代谢和代谢适应中起着至关重要的作用.
