Abstract AP32: THE METHYLTRANSFERASE EZH2 IS A VULNERABLE TARGET IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE (SCCOHT)
Notice bibliographique
Résumé
Abstract PURPOSE: SCCOHT is a rare, poorly differentiated and very deadly ovarian tumor that mainly affects young women with the median age in twenties. Recently, we and others have discovered that the genome of SCCOHT was minimally disturbed compared to common malignancies with the inactivation mutations of SMARCA4 being the only recurrent genetic alternation in SCCOHT genome. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which is the master regulator of gene transcription through controlling the accessibility of chromatin and therefore plays critical roles in many biological processes such as cell cycle control, apoptosis, and differentiation. Recently, a genetic antagonism has been observed between some SWI/SNF complex components and the histone methyltransferase EZH2 of the polycomb repressive complex 2 (PRC2), suggesting that EZH2 may be a vulnerable target in certain SWI/SNF-deficient tumor. Therefore, we aimed to determine the promise of defeating SCCOHT through targeting EZH2 in the present study. METHODS: The EZH2 protein expression was determined by immunohistochemistry on the SCCOHT tissue microarray. Cell viability, cell cycle and apoptosis were measured by crystal violet staining, FACS analysis and live cell imaging with activated caspase-3/7 staining, respectively. The proteomic profiles of SCCOHT cells were determined by Mass Spectrometry using the TMT-labeled peptide fractions. Two SCCOHT xenograft mouse models were established from BIN67 and SCCOHT1 cells, respectively, in immune-deficient mice were used for the evaluation of EPZ-6438 efficacy in vivo. RESULT: All (24/24) SCCOHT expressed abundant EZH2 protein. In comparison to other ovarian cell lines, SCCOHT cells displayed hypersensitivity to two EZH2 inhibitors (GSK126 and EPZ-6438) and EZH2 shRNA. Furthermore, EPZ-6438 induced cell cycle arrest, apoptosis and cell differentiation in SCCOHT cells, accompanying by the induction of genes involved in cell proliferation, apoptosis and differentiation. Treatment of EPZ-6438 in SCCOHT xenograft-bearing mice delayed tumor progression, improved the survival of mice. Further, re-expression of SMARCA4 suppressed the expression of EZH2 and the global level of histone H3K27 trimethylation, induced the expression of PRC2 targets that are induced by EZH2 inhibitors and triggered differentiation of SCCOHT cells. In addition, we also discovered that SCCOHT cells are hypersensitive to multiple inhibitors of histone deacetylase (HDAC), which is known to cooperate with EZH2 to silence certain target genes. Combined treatment of EPZ-6438 and Quisinostat (an HDAC inhibitor) synergistically suppressed the proliferation of SCCOHT cells. CONCLUSION: Our data suggest that EZH2 is a promising therapeutic target for fighting SCCOHT. Combined pharmacological targeting of both EZH2 and HDAC may provide a novel treatment option for SCCOHT patients. Citation Format: Yemin Wang, Shary Chen, Anthony Karnezis, Nancy Dos Santos, Pilar Ramos, Sarah Maines-Bandiera, Christine Chow, Bernard Weissman, Jeffrey Trent, David Huntsman. THE METHYLTRANSFERASE EZH2 IS A VULNERABLE TARGET IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE (SCCOHT) [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP32.
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 | 0,003 | 0,001 |
| 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 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| 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 ».