Global epigenetic regulation of microRNAs in multiple myeloma.

Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive sub...

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Autores principales: Wenjing Zhang, Yaoyu E Wang, Yu Zhang, Xavier Leleu, Michaela Reagan, Yong Zhang, Yuji Mishima, Siobhan Glavey, Salomon Manier, Antonio Sacco, Bo Jiang, Aldo M Roccaro, Irene M Ghobrial
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Publicado: Public Library of Science (PLoS) 2014
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spelling oai:doaj.org-article:cf08cdb52ee0441a9a83c818eadb3a8d2021-11-25T05:56:06ZGlobal epigenetic regulation of microRNAs in multiple myeloma.1932-620310.1371/journal.pone.0110973https://doaj.org/article/cf08cdb52ee0441a9a83c818eadb3a8d2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0110973https://doaj.org/toc/1932-6203Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2'-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM.Wenjing ZhangYaoyu E WangYu ZhangXavier LeleuMichaela ReaganYong ZhangYuji MishimaSiobhan GlaveySalomon ManierAntonio SaccoBo JiangAldo M RoccaroIrene M GhobrialPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e110973 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Wenjing Zhang
Yaoyu E Wang
Yu Zhang
Xavier Leleu
Michaela Reagan
Yong Zhang
Yuji Mishima
Siobhan Glavey
Salomon Manier
Antonio Sacco
Bo Jiang
Aldo M Roccaro
Irene M Ghobrial
Global epigenetic regulation of microRNAs in multiple myeloma.
description Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2'-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM.
format article
author Wenjing Zhang
Yaoyu E Wang
Yu Zhang
Xavier Leleu
Michaela Reagan
Yong Zhang
Yuji Mishima
Siobhan Glavey
Salomon Manier
Antonio Sacco
Bo Jiang
Aldo M Roccaro
Irene M Ghobrial
author_facet Wenjing Zhang
Yaoyu E Wang
Yu Zhang
Xavier Leleu
Michaela Reagan
Yong Zhang
Yuji Mishima
Siobhan Glavey
Salomon Manier
Antonio Sacco
Bo Jiang
Aldo M Roccaro
Irene M Ghobrial
author_sort Wenjing Zhang
title Global epigenetic regulation of microRNAs in multiple myeloma.
title_short Global epigenetic regulation of microRNAs in multiple myeloma.
title_full Global epigenetic regulation of microRNAs in multiple myeloma.
title_fullStr Global epigenetic regulation of microRNAs in multiple myeloma.
title_full_unstemmed Global epigenetic regulation of microRNAs in multiple myeloma.
title_sort global epigenetic regulation of micrornas in multiple myeloma.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/cf08cdb52ee0441a9a83c818eadb3a8d
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