E2F transcription factor-1 modulates expression of glutamine metabolic genes in mouse embryonic fibroblasts and uterine sarcoma cells

Katharina Huber; Albert Giralt; René Dreos; Helene Michenthaler; Sarah Geller; Valentin Barquissau; Dorian V Ziegler; Daniele Tavernari; Hector Gallart-Ayala; Katarina Krajina; Katharina Jonas; Giovanni Ciriello; Julijana Ivanisevic; Andreas Prokesch; Martin Pichler; Lluis Fajas

doi:10.1016/j.bbamcr.2024.119721

E2F transcription factor-1 modulates expression of glutamine metabolic genes in mouse embryonic fibroblasts and uterine sarcoma cells

Biochim Biophys Acta Mol Cell Res. 2024 Apr 3;1871(5):119721. doi: 10.1016/j.bbamcr.2024.119721. Online ahead of print.

Authors

Katharina Huber¹, Albert Giralt², René Dreos², Helene Michenthaler³, Sarah Geller², Valentin Barquissau², Dorian V Ziegler², Daniele Tavernari⁴, Hector Gallart-Ayala⁵, Katarina Krajina⁶, Katharina Jonas⁶, Giovanni Ciriello⁴, Julijana Ivanisevic⁵, Andreas Prokesch⁷, Martin Pichler⁸, Lluis Fajas⁹

Affiliations

¹ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
² Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
³ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
⁴ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Cancer Center Léman, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
⁵ Metabolomics Unit, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
⁶ Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
⁷ Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
⁸ Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Translational Oncology, II. Med. Clinics, University Hospital of Augsburg, Augsburg, Germany.
⁹ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. Electronic address: lluis.fajas@unil.ch.

PMID: 38580088
DOI: 10.1016/j.bbamcr.2024.119721

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.

Keywords: E2F1; Glutamine; MYC; SLC1A5; Uterine sarcoma; cancer metabolism.