title: miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model.
abstract: Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.
authors.affiliation: Department of Molecular Virology, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Sukhinder K
authors.initials: SK
authors.lastname: Sandhu
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Marco
authors.initials: M
authors.lastname: Galasso
authors.forename: Reid
authors.initials: R
authors.lastname: Neinast
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Santhanam
authors.forename: Mark R
authors.initials: MR
authors.lastname: Parthun
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology*; D046228:Microarray Analysis; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C530105:Ccnd1 protein, mouse; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D015850:Interleukin-6; C000715470:MAS1 protein, human; C499479:Mad protein, mouse; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D019938:Cyclin D1; D008156:Luciferases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases