TY - JOUR
T1 - Genome-wide pharmacologic unmasking identifies tumor suppressive microRNAs in multiple myeloma
AU - Bi, Chonglei
AU - Chung, Tae Hoon
AU - Huang, Gaofeng
AU - Zhou, Jianbiao
AU - Yan, Junli
AU - Ahmann, Gregory J.
AU - Fonseca, Rafael
AU - Chng, Wee Joo
PY - 2015
Y1 - 2015
N2 - Epigenetic alterations have emerged as an important cause of microRNA (miRNA) deregulation. In Multiple Myeloma (MM), a few tumor suppressive miRNAs silenced by DNA hypermethylation have been reported, but so far there are few systemic investigations on epigenetically silenced miRNAs. We conducted genomewide screening for tumor suppressive miRNAs epigenetically silenced in MM. Four Human MM Cell lines were treated with demethylating agent 5'azacytidine (5'aza). Consistently upregulated miRNAs include miR-155, miR-198, miR-135a*, miR-200c, miR-125a-3p, miR-188-5p, miR-483-5p, miR-663, and miR-630. Methylation array analysis revealed increased methylation at or near miRNA-associated CpG islands in MM patients. Ectopic restoration of miR-155, miR-198, miR-135a*, miR-200c, miR-663 and miR-483-5p significantly repressed MM cell proliferation, migration and colony formation. Furthermore, we derived a 33-gene signature from predicted miRNA target genes that were also upregulated in MM patients and associated with patient survival in three independent myeloma datasets. In summary, we have revealed important, epigenetically silenced tumor suppressive miRNAs by pharmacologic reversal of epigenetic silencing.
AB - Epigenetic alterations have emerged as an important cause of microRNA (miRNA) deregulation. In Multiple Myeloma (MM), a few tumor suppressive miRNAs silenced by DNA hypermethylation have been reported, but so far there are few systemic investigations on epigenetically silenced miRNAs. We conducted genomewide screening for tumor suppressive miRNAs epigenetically silenced in MM. Four Human MM Cell lines were treated with demethylating agent 5'azacytidine (5'aza). Consistently upregulated miRNAs include miR-155, miR-198, miR-135a*, miR-200c, miR-125a-3p, miR-188-5p, miR-483-5p, miR-663, and miR-630. Methylation array analysis revealed increased methylation at or near miRNA-associated CpG islands in MM patients. Ectopic restoration of miR-155, miR-198, miR-135a*, miR-200c, miR-663 and miR-483-5p significantly repressed MM cell proliferation, migration and colony formation. Furthermore, we derived a 33-gene signature from predicted miRNA target genes that were also upregulated in MM patients and associated with patient survival in three independent myeloma datasets. In summary, we have revealed important, epigenetically silenced tumor suppressive miRNAs by pharmacologic reversal of epigenetic silencing.
KW - Epigenetics/MicroRNA
KW - Myeloma
KW - Tumor suppressor
UR - http://www.scopus.com/inward/record.url?scp=84944462954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944462954&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.4769
DO - 10.18632/oncotarget.4769
M3 - Article
C2 - 26164366
AN - SCOPUS:84944462954
SN - 1949-2553
VL - 6
SP - 26508
EP - 26518
JO - Oncotarget
JF - Oncotarget
IS - 28
ER -