57P - Deciphering the role of E2F transcription factor-1 in glutamine metabolism

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.