microRNA-dependent modulation of histone acetylation in Waldenstrom macroglobulinemia.
Waldenström macroglobulinemia (WM) cells present with increased expression of microRNA-206 (miRNA-206) and reduced expression of miRNA-9*. Predicted miRNA-206- and -9*-targeted genes include histone deacetylases (HDACs) and histone acetyl transferases (HATs), indicating that these miRNAs may play a role in regulating histone acetylation. We were able to demonstrate that primary WM cells are characterized by unbalanced expression of HDACs and HATs, responsible for decreased acetylated histone-H3 and -H4, and increased HDAC activity. We next examined whether miRNA-206 and -9* modulate the aberrant expression of HDAC and HATs in WM cells leading to increased transcriptional activity. We found that restoring miRNA-9* levels induced toxicity in WM cells, supported by down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4. These, together with inhibited HDAC activity, led to induction of apoptosis and autophagy in WM cells. To further confirm that miRNA-9*-dependent modulation of histone acetylation is responsible for induction of WM cytotoxicity, a novel class of HDAC inhibitor (LBH589) was used; we confirmed that inhibition of HDAC activity leads to toxicity in this disease. These findings confirm that histone-modifying genes and HDAC activity are deregulated in WM cells, partially driven by the aberrant expression of miRNA-206 and -9* in the tumor clone.
Roccaro
Aldo M
AM
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Sacco
Antonio
A
Jia
Xiaoying
X
Azab
Abdel Kareem
AK
Maiso
Patricia
P
Ngo
Hai T
HT
Azab
Feda
F
Runnels
Judith
J
Quang
Phong
P
Ghobrial
Irene M
IM
D000107:Acetylation; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; C546087:MIRN206 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D051548:Histone Acetyltransferases; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases