E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells

Area of Science:

• Molecular Biology
• Cancer Metabolism
• Epigenetics

Background:

• Cancer cells exhibit altered energy metabolism, relying on aerobic glycolysis.
• Sirtuin 6 (Sirt6) is a histone deacetylase known to inhibit glycolysis.
• The role of E2F1 in regulating cancer cell metabolism, particularly glycolysis, is not fully understood.

Purpose of the Study:

• To investigate the hypothesis that E2F1 enhances glycolysis and suppresses Sirt6 expression.
• To elucidate the molecular mechanisms by which E2F1 regulates Sirt6 and glycolysis.
• To explore the potential oncogenic role of E2F1 in cancer metabolism.

Main Methods:

• Over-expression and siRNA-mediated knockdown of E2F1 in bladder and prostate cancer cell lines.
• Measurement of glucose uptake and lactate production.
• Chromatin immunoprecipitation (ChIP) assays to assess E2F1 binding to the Sirt6 promoter.
• Reporter gene assays to evaluate Sirt6 promoter activity.
• Analysis of E2F1 acetylation by Histone Deacetylase 1 (HDAC1) and the effect of HDAC inhibitors.

Main Results:

• E2F1 over-expression significantly increased glucose uptake and lactate production, while suppressing Sirt6 expression and function.
• E2F1 directly bound to the Sirt6 promoter, inhibiting its activity under normoxic and hypoxic conditions.
• HDAC1-mediated deacetylation of E2F1 diminished its transcriptional suppression of the Sirt6 promoter.
• HDAC inhibitor treatment increased E2F1 acetylation and suppressed Sirt6 transcription.

Conclusions:

• E2F1 acts as an oncogene by enhancing aerobic glycolysis through the suppression of Sirt6 transcription.
• E2F1's regulation of Sirt6 involves direct promoter binding and is influenced by HDAC1-mediated acetylation.
• These findings reveal a novel mechanism linking E2F1, Sirt6, and cancer cell energy metabolism.