| Title |
Combinatorial Treatment of DNA and Chromatin-Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines
|
|---|---|
| Published in |
PLOS ONE, September 2012
|
| DOI | 10.1371/journal.pone.0043720 |
| Pubmed ID | |
| Authors |
Venugopal Thayanithy, ChangWon Park, Aaron L. Sarver, Reena V. Kartha, Derek M. Korpela, Ashley J. Graef, Clifford J. Steer, Jaime F. Modiano, Subbaya Subramanian |
| Abstract |
Downregulation of microRNAs (miRNAs) at the 14q32 locus stabilizes the expression of cMYC, thus significantly contributing to osteosarcoma (OS) pathobiology. Here, we show that downregulation of 14q32 miRNAs is epigenetically regulated. The predicted promoter regions of miRNA clusters at 14q32 locus showed no recurrent patterns of differential methylation, but Saos2 cells showed elevated histone deacetylase (HDAC) activity. Treatment with 4-phenylbutyrate increased acetylation of histones associated with 14q32 miRNAs, but interestingly, robust restoration of 14q32 miRNA expression, attenuation of cMYC expression, and induction of apoptosis required concomitant treatment with 5-Azacytidine, an inhibitor of DNA methylation. These events were associated with genome-wide gene expression changes including induction of pro-apoptotic genes and downregulation of cell cycle genes. Comparable effects were achieved in human and canine OS cells using the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) and the DNA methylation inhibitor Zebularine (Zeb), with significantly more pronounced cytotoxicity in cells whose molecular phenotypes were indicative of aggressive biological behavior. These results suggested that the combination of these chromatin-modifying drugs may be a useful adjuvant in the treatment of rapidly progressive OS. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Germany | 1 | 50% |
| Italy | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Scientists | 1 | 50% |
| Members of the public | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 66 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 3 | 5% |
| Russia | 1 | 2% |
| Germany | 1 | 2% |
| Unknown | 61 | 92% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 16 | 24% |
| Student > Postgraduate | 10 | 15% |
| Other | 10 | 15% |
| Student > Ph. D. Student | 6 | 9% |
| Student > Master | 5 | 8% |
| Other | 9 | 14% |
| Unknown | 10 | 15% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 13 | 20% |
| Medicine and Dentistry | 12 | 18% |
| Agricultural and Biological Sciences | 12 | 18% |
| Veterinary Science and Veterinary Medicine | 9 | 14% |
| Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
| Other | 8 | 12% |
| Unknown | 10 | 15% |