SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia

A rapid method for quantifying free and bound acetate based on alkylation and GC-MS analysis

“…For example, acetylation of histones promotes gene transcription and a correlation between degree of histone acetylation and tumor aggressiveness has been observed [40]. Further evidence for the importance of acetylation homeostasis in cancer progression comes from the observation that disrupting acetylation dynamics by inhibiting deacetylases (i.e., HDACs, sirtuins) leads to potent induction of cancer cell death [12, 15]. While several aspects of acetylation are being extensively studied, much remains unknown about absolute pool sizes and turnover of acetate bound to bio-molecules in the various cell compartments, let alone how they are affected by tumor-relevant conditions.…”

“…Acetylation is especially prominent on histones and is important for controlling gene expression [11–13]. Based on this, it is not surprising that acetyl-transferases, sirtuins, and histone deacetylases have been found to play important roles in tumorigenesis [14, 15]. …”

Epigenetic regulators: multifunctional proteins modulating hypoxia-inducible factor-α protein stability and activity

“…Several environmental stresses including hypoxia reduces intracellular NAD + levels in mammalian cells, which results in decreased deacetylase activity of SIRT [34]. SIRT1 is the most studied SIRT family member in gene regulation, but its effect on HIF-1 transcriptional activity is still under debate [34, 63–66]. Dioum et al reported that SIRT1 selectively interacts with HIF-2α and deacetylates HIF-2α to increase its transcriptional activity in human hepatoma Hep3B cells [65].…”

“…Forced expression of SIRT1 decreases hypoxia-induced expression of PDK1, VEGFA, and CA9, and impairs tumor growth in xenograft mice [34]. Subsequent studies indicate that SIRT1 indirectly acts on HIF-1 transcriptional activity through HIF-1α protein stability [63, 64]. Genetic or pharmacological inhibition of SIRT1 increases the acetylation of HIF-1α to decrease stabilization of HIF-1α protein and HIF-1-dependent gene expression in human cancer cell lines.…”

The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression

“…The effect of phosphorylation on the stability of HIF-1α depends on the kinase involved [18,19]; it has been reported that HIF-1α is destabilized by GSK-3β [20] and PLK3 [21], but stabilized by CDK1 [22] and ATM [23]. The reversal of these PTMs, such as deubiquitination [24], deSUMOylation [25], deacetylation [26,27], and demethylation [17], also regulates HIF-1α stability. As for phosphatase regulating HIF-1α, SHP-1 decreases HIF-1α’s expression although direct dephosphorylation of HIF-1α by SHP-1 has not been determined [28].…”