Abstract B01: Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways
Notice bibliographique
Résumé
Abstract Despite advances in treatment, Colorectal cancer (CRC) remains a leading cause of cancer related deaths in North America. Most CRCs contain a subset of self-renewing colon cancer-initiating cells (CC-ICs) responsible for tumor initiation and maintenance. CC-ICs are relatively chemoresistant as compared to the bulk tumor cells, however the mechanisms of this chemoresistance are poorly understood. An increasing amount of evidence suggests that epigenetic regulators may be playing a central role in driving CC-IC chemoresistance; one such example being histone acetyltransferase (HAT1), which plays an important role in cancer cell proliferation and response to DNA damage (Xue et al, Int J Clin Exp Pathol, 2014). The cytoplasmic HAT1/HAT2 complex acetylates histone H4 on lysine residues 5 and/or 12. Acetylated histone H4 is then bound to histone H3 and the complex is transported to the nucleus where the HAT1/HAT2 complex aids in depositing H3/H4 onto DNA (Parthum, Oncogene, 2007). In normal colon, HAT1 is predominantly localized to the nucleus in cells at the crypt base, whereas in primary and metastatic colorectal tumors, HAT1 expression is upregulated, mostly cytoplasmic, and diffuse throughout the tissue (Seiden-Long et al, Oncogene, 2006). To investigate HAT1 localization in our primary derived CC-IC enriched cell lines we used protein fractionation and western blot analysis. In our samples, we consistently see elevated cytoplasmic HAT1 expression compared to nuclear extracts. To determine the effect of the loss of HAT1 on CC-IC viability we infected our CC-IC enriched cell lines with lentiviral shRNA to knockdown HAT1. We observed no changes in growth or cell viability at baseline between the HAT1 knockdown cells and controls, however, previous studies have shown that HAT1 knockdown increases cancer cell sensitivity to DNA damaging agents such as camptothecin (CPT) or methyl methane sulfonate (MMS) by controlling Rad52 degradation, accumulating replication block double stranded breaks and prolonging G2 arrest, indicating that it is important for DNA repair processing (Barman et al, BBRC, 2006). To determine whether HAT1 contributes to CC-IC chemoresistance we treated our HAT1 knockdown cells with standard of care (SOC) chemotherapy (oxaliplatin). Viability assays showed that after 10 days of treatment there is a 40% decrease in cell viability compared to controls. To investigate whether the decrease in cell viability seen in HAT1 knockdown cells is due to an increase in DNA damage we stained cells for DNA damage marker γH2AX. Immunofluorescence analysis revealed a higher level of γH2AX staining in HAT1 knockdown cells treated with SOC chemotherapy. To examine the effects of HAT1 knockdown on CC-IC function when combined with SOC chemotherapy, we preformed a limiting dilution assay. Untreated CC-IC enriched HAT1 knockdown cells had no significant difference in CC-IC frequency, however, treating these cells with SOC chemotherapy resulted in a decrease in CC-IC frequency in vitro (212.2 vs 52.8). Our current research suggests that HAT1 plays an important role in CC-IC function, chemoresistance and response to DNA damage. We are further investigating HAT1 as a potential therapeutic target in order to improve outcomes for CRC patients. Citation Format: Lauren Agro, Cherry Leung, Yadong Wang, Evelyne Lima-Fernandes, Catherine O'Brien. Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B01.
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 | 0,001 | 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 | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 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 ».