Abstract 57P
Background
Metabolic reprogramming is considered as a hallmark of cancer and is clinically exploited as a target for therapy. The E2F transcription factor-1 (E2F1) regulates metabolic pathways and operates as an oncogene or tumor suppressor as evident by the observation that E2f1-knockout mice develop spontaneous tumors. This discrepancy warrants a detailed investigation how E2F1’s metabolic functions control cellular proliferation and tumor growth.
Methods
Taking advantage of mouse embryonic fibroblasts (MEFs), isolated from E2f1-wild-type (E2f1+/+) and E2f1-knock-out (E2f1-/-) mice as well as transcriptomic profiles (TCGA Pan-cancer study), we investigated the biological outcomes of altered E2F1 expression on glutamine metabolism.
Results
Our data indicate that E2F1 binds the promoter of several glutamine metabolic genes. Interestingly, the gene expression levels of genes in the glutamine metabolic pathway are strongly increased in mouse embryonic fibroblasts lacking E2F1 compared to E2f1+/+ MEFs. In addition, we confirm that E2f1-/- MEFs are more efficient in metabolizing glutamine and producing precursors for proliferation. Mechanistically, we observe a co-occupancy of E2F1 and MYC on glutamine metabolic promoters, increased MYC binding after E2F1 depletion and silencing of MYC decreases the expression of glutamine metabolic genes in E2f1-/- MEFs, suggesting that MYC contributes to increased glutamine metabolic gene expression in E2f1-/- MEFs. These features have also been observed in human patient samples in a screen of 21 different cancer types and showed high relevance in uterine carcinosarcoma and soft tissue sarcomas.
Conclusions
These results confirm increased proliferation upon E2F1 loss, which is dependent on glutamine metabolism. Altogether, our results suggest that E2F1 is a regulator of glutamine metabolism and highlights potentially new targets for cancer interventions.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
M. Pichler and L. Fajas.
Funding
Austrian Science Fund (J4597-B), Swiss National Science Foundation grant (31003A_143369).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
63P - Role of EGFR-targeted therapy in the treatment of advanced and metastatic cervical cancers
Presenter: Abhishek Krishna
Session: Cocktail & Poster Display session
Resources:
Abstract
64P - Isothermal chemical KRAS denaturation assay for monitoring stability and inhibitors interactions
Presenter: Randa Mahran
Session: Cocktail & Poster Display session
Resources:
Abstract
65P - Influence of efflux and uptake transporters on the pharmacokinetics of the SYK inhibitors entospletinib and lanraplenib
Presenter: Nancy Loos
Session: Cocktail & Poster Display session
Resources:
Abstract
66P - Targeting allosteric sites on PDK-1 and PLK-1 with bioactive compounds from <italic>Daucus carota</italic> as a potential therapy for triple-negative breast cancer
Presenter: Kayode Raheem
Session: Cocktail & Poster Display session
Resources:
Abstract
67P - Molecular testing and treatment of patients with advanced solid tumors harboring an NTRK gene fusion: Interim results of the REALTRK registry
Presenter: Corinne Vannier
Session: Cocktail & Poster Display session
Resources:
Abstract
68P - Investigating CDK4/6 palbociclib resistance mechanisms in MCF7 breast cancer cell line
Presenter: Heloise Beutier
Session: Cocktail & Poster Display session
Resources:
Abstract
69P - Osimertinib is selective against NSCLC cells and modulates the multidrug-resistant phenotype in patient-derived cell cultures and co-cultures of NSCLC cells and fibroblasts
Presenter: Sofija Jovanović Stojanov
Session: Cocktail & Poster Display session
Resources:
Abstract
71P - Molecular Tumor Board at the European Institute of Oncology: An early Italian precision oncology experience
Presenter: Edoardo Crimini
Session: Cocktail & Poster Display session
Resources:
Abstract
72P - MDM alterations in patients with advanced or metastatic cancers
Presenter: Iwona Lugowska
Session: Cocktail & Poster Display session
Resources:
Abstract
73P - Automated detection of typical and atypical mitotic figures for improving survival prediction in breast cancer
Presenter: Saima Ben Hadj
Session: Cocktail & Poster Display session
Resources:
Abstract