PMID- 30194076 OWN - NLM STAT- MEDLINE DCOM- 20181127 LR - 20211204 IS - 1790-6245 (Electronic) IS - 1109-6535 (Print) IS - 1109-6535 (Linking) VI - 15 IP - 5 DP - 2018 Sep-Oct TI - Whole-transcriptomic Profile of SK-MEL-3 Melanoma Cells Treated with the Histone Deacetylase Inhibitor: Trichostatin A. PG - 349-364 LID - 10.21873/cgp.20094 [doi] AB - BACKGROUND: Malignant melanoma cells can rapidly acquire phenotypic properties making them resistant to radiation and mainline chemotherapies such as decarbonize or kinase inhibitors that target RAS-proto-oncogene independent auto-activated mitogen-activated protein kinases (MAPK)/through dual specificity mitogen-activated protein kinase (MEK). Both drug resistance and inherent transition from melanocytic nevi to malignant melanoma involve the overexpression of histone deacetylases (HDACs) and a B-Raf proto-oncogene (BRAF) mutation. MATERIALS AND METHODS: In this work, the effects of an HDAC class I and II inhibitor trichostatin A (TSA) on the whole transcriptome of SK-MEL-3 cells carrying a BRAF mutation was examined. RESULTS: The data obtained show that TSA was an extremely potent HDAC inhibitor within SK-MEL-3 nuclear lysates, where TSA was then optimized for appropriate sub-lethal concentrations for in vitro testing. The whole-transcriptome profile shows a basic phenotype dominance in the SK-MEL-3 cell line for i) synthesis of melanin, ii) phagosome acidification, iii) ATP hydrolysis-coupled proton pumps and iv) iron transport systems. While TSA did not affect the aforementioned major systems, it evoked a dramatic change to the transcriptome: reflected by a down-regulation of 810 transcripts and up-regulation of 833, with fold-change from -15.27 to +31.1 FC (p<0.00001). Largest differentials were found for the following transcripts: Up-regulated: Tetraspanin 13 (TSPAN13), serpin family i member 1 (SERPINI1), ATPase Na+/K+ transporting subunit beta 2 (ATP1B2), nicotinamide nucleotide adenylyl transferase 2 (NMNAT2), platelet-derived growth factor receptor-like (PDGFRL), cytochrome P450 family 1 subfamily A member 1 (CYP1A1), prostate androgen-regulated mucin-like protein 1 (PARM1), secretogranin II (SCG2), SYT11 (synaptotagmin 11), rhophilin associated tail protein 1 like (ROPN1L); down-regulated: polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), carbonic anhydrase 14 (CAXIV), BCL2-related protein A1 (BCL2A1), protein kinase C delta (PRKCD), transient receptor potential cation channel subfamily M member 1 (TRPM1), ubiquitin associated protein 1 like (UBAP1L), glutathione peroxidase 8 (GPX8), interleukin 16 (IL16), tumor protein p53 (TP53), and serpin family H member 1 (SERPINH1). There was no change to any of the HDAC transcripts (class I, II and IV), the sirtuin HDAC family (1-6) or the BRAF proto-oncogene v 599 transcripts. However, the data showed that TSA down-regulated influential transcripts that drive the BRAF-extracellular signal-regulated kinase (ERK)1/2 oncogenic pathway (namely PRKCD and MYC proto-oncogene which negatively affected the cell-cycle distribution. Mitotic inhibition was corroborated by functional pathway analysis and flow cytometry confirming halt at the G(2) phase, occurring in the absence of toxicity. CONCLUSION: TSA does not alter HDAC transcripts nor BRAF itself, but down-regulates critical components of the MAPK/MEK/BRAF oncogenic pathway, initiating a mitotic arrest. CI - Copyright(c) 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved. FAU - Mazzio, Elizabeth A AU - Mazzio EA AD - College of Pharmacy and Pharmaceutical Sciences, Florida A and M University, Tallahassee, FL, U.S.A. FAU - Soliman, Karam F A AU - Soliman KFA AD - College of Pharmacy and Pharmaceutical Sciences, Florida A and M University, Tallahassee, FL, U.S.A. karam.soliman@famu.edu. LA - eng GR - G12 MD007582/MD/NIMHD NIH HHS/United States GR - P20 MD006738/MD/NIMHD NIH HHS/United States PT - Journal Article PL - Greece TA - Cancer Genomics Proteomics JT - Cancer genomics & proteomics JID - 101188791 RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Hydroxamic Acids) RN - 0 (MAS1 protein, human) RN - 0 (Neoplasm Proteins) RN - 0 (Proto-Oncogene Mas) RN - 3X2S926L3Z (trichostatin A) RN - EC 2.7.11.1 (BRAF protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 3.5.1.98 (Histone Deacetylases) SB - IM MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm/genetics MH - Gene Expression Regulation, Neoplastic/drug effects MH - Histone Deacetylase Inhibitors/*therapeutic use MH - Histone Deacetylases/genetics MH - Humans MH - Hydroxamic Acids/*therapeutic use MH - MAP Kinase Signaling System/drug effects MH - Melanoma/*drug therapy/genetics/pathology MH - Neoplasm Proteins/genetics MH - Proto-Oncogene Mas MH - Proto-Oncogene Proteins B-raf/*genetics MH - Transcriptome PMC - PMC6199573 OTO - NOTNLM OT - BRAF mutation OT - MAPK/MEK/BRAF oncogenic pathway OT - Melanoma cells OT - SK-MEL-3 OT - histone deacetylase inhibitor OT - mitotic arrest OT - transcriptomic profile OT - trichostatin A EDAT- 2018/09/09 06:00 MHDA- 2018/11/28 06:00 PMCR- 2018/09/03 CRDT- 2018/09/09 06:00 PHST- 2018/06/08 00:00 [received] PHST- 2018/07/09 00:00 [revised] PHST- 2018/07/16 00:00 [accepted] PHST- 2018/09/09 06:00 [entrez] PHST- 2018/09/09 06:00 [pubmed] PHST- 2018/11/28 06:00 [medline] PHST- 2018/09/03 00:00 [pmc-release] AID - 15/5/349 [pii] AID - 10.21873/cgp.20094 [doi] PST - ppublish SO - Cancer Genomics Proteomics. 2018 Sep-Oct;15(5):349-364. doi: 10.21873/cgp.20094.