Abstract
The fast proliferation of cancer cells requires reprogramming of its energy metabolism with aerobic glycolysis as a major energy source. Sirt6, a class III histone deacetylase, has been shown to down regulate glycolysis by inhibiting the expression of several key glycolytic genes. Based on the published study on the metabolic phenotype of E2F1 -/- mice and SIRT6 -/- mice, we hypothesize that E2F1 enhances glycolysis and inhibits the expression of Sirt6. Indeed, over-expressing of E2F1, but not its DNA binding deficient mutant, significantly enhanced glucose uptake and lactate production in bladder and prostate cancer cell lines. E2F1 over-expression also suppressed Sirt6 expression and function. Moreover, E2F1 directly bound to Sirt6 promoter and suppressed Sirt6 promoter activity under both normoxic and hypoxic culture conditions. E2F1 siRNA blocked the up-regulation of E2F1 under hypoxia, increased Sirt6 expression and decreased glycolysis compared to those of scrambled siRNA transected cells. Furthermore, HDAC1 deacetylated E2F1 and diminished its transcription suppression of Sirt6 promoter. Treatment with the HDAC inhibitor, trichostatin A (TSA), suppressed Sirt6 promoter activity with increased binding of acetylated E2F1 to Sirt6 promoter. Mutating the E2F1 binding site on the proximal Sirt6 promoter abolished the suppression of Sirt6 transcription by TSA. These data indicate a novel oncogenic role of E2F1, i.e. enhancing glycolysis by suppressing Sirt6 transcription.
Highlights
As a founding member of E2F family of transcription factors, E2F1 participates in regulating cell-cycle progression, cell differentiation, DNA repair, and apoptosis
To test further that SIRT6 is involved in the enhanced glycolysis after E2F1 over-expression, glucose uptake and lactate production were compared among pcDNA3.1 vector transfected PC3 cells and PC3 cells over-expressing SIRT6, E2F1, or both
Utilizing prostate cancer and bladder cancer cell lines, our data support our hypothesis that E2F1 suppresses SIRT6 transcription and facilities cancer cell glycolysis
Summary
As a founding member of E2F family of transcription factors, E2F1 participates in regulating cell-cycle progression, cell differentiation, DNA repair, and apoptosis. Enhanced aerobic glycolysis was mostly observed in BAT and muscle [3] This metabolic phenotype is in direct contrast of the E2F1 -/- mice, suggesting that E2F1 may down regulate SIRT6 www.impactjournals.com/oncotarget to facilitate glucose metabolism. The only published report on SIRT6 regulation to date came from studies with a mouse hepatoma cell line, Hepa, which showed that a complex of SIRT1, FOXO3a and NRF1 up-regulated SIRT6 upon nutritional stress [6] It is unclear whether this complex directly regulated SIRT6 transcription at the promoter region. In addition to inhibiting aerobic glycolysis, SIRT6 has been shown to promote genomic stability through facilitating DNA repair [13,14,15], attenuate inflammation through damping NF-κB-dependent gene expression [16], and function like a tumor suppressor through repressing Warburg effect in cancer cells [17]. Deacetylation of E2F1 by HDAC1 facilitated SIRT6 transcription by dissociating E2F1 from the SIRT6 promoter region
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