Strategies to Re-Express Epigenetically-Silenced Tumor Suppressor Genes Converge on the Requirement for Inhibition of the Histone Methyltransferase SUV39H1.
Notice bibliographique
Résumé
Abstract Gene silencing mediated by aberrant promoter DNA hypermethylation represents a key mechanism by which tumor suppressor gene expression is silenced in cancer and it is associated with multiple repressive histone modifications. Histone H3 lysine 9 (H3K9) methylation is a key repressive chromatin modification with important implications for regulating cell proliferation, differentiation, and gene expression. SUV39H1 is a methyltransferase that catalyzes the addition of trimethyl groups to H3K9. SUV39H1 is associated with regions of hypermethylated CpG islands, with repressive complexes, such as RB/E2F, and with DNA-binding proteins involved in leukemogenesis, such as AML1 and PML-RAR, where its H3K9 trimethylation activity promotes heterochromatin formation and gene silencing. We studied the requirement of SUV39H1 in the epigenetic silencing of heavily methylated tumor suppressor genes p15INK4B and E-cadherin in acute myeloid leukemia (AML). Treatment of AML cell lines AML193, KG1a, and Kasumi with the DNA methyltransferase (DNMT) inhibitor 5-Aza-2’-deoxycytidine (5-Aza-dC) induces p15INK4B and E-cadeherin re-expression in association with dramatic decreases in p15INK4B and E-cadherin promoter DNA methylation and marked reductions in the levels of SUV39H1 and H3K9 trimethylation at these promoters. Interestingly, treatment of these cell lines with SUV39H1 shRNA, or the SUV39H1 inhibitor chaetocin, also induces p15INK4B and E-cadherin re-expression and H3K9 demethylation, without affecting promoter DNA methylation. Thus, re-expression of hypermethylated tumor suppressors requires histone H3K9 demethylation, which can be achieved indirectly by decreasing the amount of SUV39H1 associated with the promoter using 5-Aza-dC, or directly by inhibiting SUV39H1 expression or activity without requiring promoter DNA demethylation. Furthermore, we found that SUV39H1 shRNA or chaetocin in combination with 5-Aza-dC acts synergistically to re-express epigenetically silenced p15INK4B and E-cadherin in AML cell lines. Treatment of primary human AML blasts obtained from two patients with combinations of 5-Aza-C and chaetocin also results in synergistic re-expression of p15INK4B and E-cadherin (2–6 fold increase with 5-Aza-C or chaetocin treatment vs. 11–14 fold increase with co-treatment). Our study has important implications for developing novel epigenetic therapies of relevance to AML as it suggests that the re-expression of tumor suppressor genes silenced by aberrant promoter DNA hypermethylation converges on the requirement for SUV39H1 and H3K9 methylation inhibition but not promoter DNA demethylation. Our finding that SUV39H1 inhibition may function synergistically with DNMT inhibitors to enhance gene reactivation and chromatin changes also highlights the needs for developing more inhibitors of histone methyltransferases and for performing detailed drug interaction studies to identify the best drug combinations for optimal epigenetic therapies.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».