Abstract LB-157: Chromatin alterations induce C-MYC and BRD4 downregulation in pediatric sarcoma
Bibliographic record
Abstract
Abstract Sarcoma accounts for 15% of all pediatric cancers diagnosed every year. Refractory patients have a poor prognosis with a 5-year survival rate of 10%, demonstrating the need for development of new therapeutic approaches. Epigenetic events, including DNA methylation and post-translational histone modifications (such as histone acetylation), are responsible for silencing tumor suppressor genes and overexpressing oncogenes. In sarcomas, a better understanding of epigenetic alterations is needed to develop new epigenetic targeted therapies. Several epigenetics drugs have demonstrated anticancer activity against sarcoma cell lines but the identification of a specific target is still missing. We demonstrated that targeting histone acetylation may represent a specific epigenetic mark in pediatric sarcomas. We identified that proscillaridin A, a newly defined epigenetic drug, has epigenetic and anticancer effects on osteosarcoma (U2OS) and rhabdomyosarcoma (RD) cell lines. Our findings show a decrease of histone 3 acetylation on specific lysine residues after a 48h-treatment with proscillaridin A at 5 nM, a clinically relevant dose. These effects correlate with downregulation of histone acetylation associated proteins such as bromodomain BRD4 and oncogene C-MYC. A 48h-treatment with proscillaridin A produces a G2/M block and a reduction in the clonogenic potential of both U2OS and RD cells with IC50 value of approximately 6 nM. Interestingly, remaining colonies of RD cells fully lost their abilities to growth after drug removal, suggesting a long-term epigenetic reprograming. We demonstrated that proscillaridin A epigenetic effects occurred through calcium signaling since its mechanism of action may be dependent on calcium-calmodulin kinase activity.These promising results illustrate the epigenetic and anticancer potential of proscillaridin A against pediatric sarcoma. Additional experiments are currently ongoing in order to further characterize the mechanism of action of proscillaridin A in vitro and in vivo. Citation Format: Elodie Da Costa, Gregory Armaos, Simon Jacques-Ricard, Annie Beaudry, Noël Raynal. Chromatin alterations induce C-MYC and BRD4 downregulation in pediatric sarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-157.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".