combinatorial treatment of dna and chromatin-modifying drugs cause cell death in human and canine osteosarcoma cell linesdna和chromatin-modifying药物组合治疗导致人类和犬类骨肉瘤细胞株的细胞死亡.pdfVIP

Combinatorial Treatment of DNA and Chromatin- Modifying Drugs Cause Cell Death in Human and Canine Osteosarcoma Cell Lines 1 2 3 4 5 Venugopal Thayanithy , ChangWon Park , Aaron L. Sarver , Reena V. Kartha , Derek M. Korpela , Ashley J. Graef5, Clifford J. Steer2,6, Jaime F. Modiano3,5, Subbaya Subramanian1,3* 1 Department of Surgery, University of Minnesota, Minneapolis, Minnesota, United States of America, 2 Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America, 3 Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America, 4 Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America, 5 Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota, United States of America, 6 Department of Genetics, Cell Biology Development, University of Minnesota, Minneapolis, Minnesota, United States of America 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 w