Abstract B01: Histone acetyltransferase 1 contributes to colon cancer initiating cell chemoresistance through DNA damage repair pathways
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".