Epigenetic mechanisms have been implicated in many physiological and pathophysiological processes. Among these, histone modifications including methylation, phosphorylation, acetylation and ubiquitination, significantly modify gene expression. In cancer, specific abnormal epigenetic changes are thought to impart tumor cells with properties that facilitate their survival.1 Recently, a new study uncovered a novel mechanism regulating epigenetic changes of importance in cancer. Briefly, a sequence of post-translational modifications triggered by changes in glucose levels were identified to positively impact tumor sphere formation and tumor engraftment.2
Histone acetylation is generally associated with an increase in gene transcription.3 Formation of this epigenetic mark is catalyzed by histone acetyl transferases (HATs), which allocate acetyl groups from Acetyl-CoA to lysine residues. Physiological triggers may modulate the type and frequency of histone epigenetic marks. For example, increased glucose level is known to induce histone acetylation in yeast.4 Nevertheless, the mechanisms underlying recruitment of HATs by glucose have not been elucidated.
In a recent study, Zhang et al. discovered that ubiquitination of various lysine (K) residues in Histone 3 (H3) is induced by glucose in cell lines. They identified NEDD4, an E3 ligase with known cytoplasmic and nuclear activity, as the enzyme responsible for H3 ubiquitination at key lysine residues. Interestingly, NEDD’s activity was dependent on its phosphorylation at specific tyrosine residues (Y43/585) and these marks were also induced by glucose.
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-Immunohistochemistry-NBP2-45400-img0002.jpg) |
Immunohistochemistry-Paraffin: NEDD4 Antibody [NBP1-40112]-Analysis of anti-NEDD4 antibody with human breast |
Immunohistochemistry: IL-1 alpha/IL-1F1 Antibody (2F8) [NBP2-45400]-Analysis of Human breast tissue.(Heat-induced epitope retrieval by10mM citric buffer, pH6.0, 120C for 3min) |
Investigators hypothesized that ubiquitination marks in H3 may favor recruitment of HATs for acetylation of lysine. As in yeast, glucose induced the acetylation of specific lysine residues in H3. Stably expressed H3 ubiquitin-deficient mutants at key lysine residues including K23, 36 and 37 were not acetylated at K9/14. Additionally, kinetic studies demonstrated that the glucose-induced ubiquitination of H3 precedes its acetylation at K9. Therefore, demonstrating a relationship between a pre-existent ubiquitin modification as a requisite for acetylation of lysine residues in H3.
GCN5 was identified as the HAT enzyme recruited by NEDD4 to acetylate H3 in response to glucose. Importantly, glucose-induced histone acetylation by GCN5 targeted gene transcription start sites (TSS), thus influencing the expression of many different genes involved in cancer signaling pathways, including IL1a, IL1b and GCLM. To understand the biological significance of these epigenetic marks, investigators used tumor sphere and engraftment assays. Phosphorylated NEDD4 and GCN5 were required for the maintenance of tumor sphere numbers. Moreover, NEDD4 was critical for tumor engraftment and tumorigenicity.
Therefore, the findings from this study suggest that in addition to the direct metabolic role of glucose for tumor growth and maintenance, glucose also influences the transcriptome of cancer cells, potentially programing these cells for survival. The Glucose/NEDD4/GCN5 pathway could serve as a useful target for cancer treatment.
Learn more in our cancer research area.
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