miR-92a-3p and MYCBP2 are involved in MS-275-induced and c-myc-mediated TRAIL-sensitivity in melanoma cells.
Increasing evidence has demonstrated that in several tumors c-myc acts either as an oncogène or as a proapoptotic agent, depending on binding partner interactions. Recently, we showed that up-regulation of this gene by the histone deacetylase inhibitor MS-275 was responsible for sensitization to TRAIL-induced apoptosis through c-FLIP repression in melanoma. The present study aimed at investigating whether, in addition to inducing H3 hyperacetylation at the c-myc promoter, MS-275 could enhance cell death through the regulation of miRNAs involved in apoptosis, such as the miR-17-92 cluster. Following MS-275 treatment, a decrease in miR-92a-3p was observed either in TRAIL-resistant or TRAIL-sensitive cutaneous and uveal melanoma cells. Prediction tools revealed that miR-92a-3p targeted MYCBP2. Gain- and loss-of-function experiments showed that the 3'-UTR of MYCBP2 mRNA was the target of miR-92a-3p, as ectopic expression of miR-92a-3p resulted in MYCBP2 downregulation whereas miR-92a-3p knockdown markedly increased the expression of MYCBP2. Silencing of MYCBP2 counteracted the pro-apoptotic effects exerted by the down-regulation of miR-92a-3p and prevented c-myc-induced repression of c-FLIP, indicating a pivotal role of MYCBP2 as a mediator of miR-92a-3p and c-myc function. Together, our findings indicate that the MS-275-triggered downregulation of the oncogenic miR-92a-3p- which leads to the overexpression of its target gene MYCBP2 - is an event required for the enhanced susceptibility of melanoma cells to TRAIL-mediated apoptosis. Our data illustrate another epigenetic mechanism activated by MS-275 at the post-transcriptional level in melanoma, in addition to its best-known effects at the transcriptional level.
Department of Biomedical Sciences and of Morphological and Functional Images, University of Messina, Messina, Italy.
Mario
M
Venza
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
Maria
M
Visalli
Department of Human Pathology of Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy; Scylla Biotech Srl, University of Messina, Messina, Italy.
Concetta
C
Beninati
Department of Human Pathology of Adult and Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy.
Salvatore
S
Benfatto
Charybdis Vaccines Srl, University of Messina, Messina, Italy.
Diana
D
Teti
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. Electronic address: isavenza@gmail.com.
Isabella
I
Venza
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C541874:MIRN92 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C118739:entinostat; C114022:MYCBP2 protein, human; D044767:Ubiquitin-Protein Ligases
Apoptosis; MS-275; MYCBP2; Melanoma; miR-92a-3p