Epigenetic silencing of tumor suppressor miR-3151 contributes to Chinese chronic lymphocytic leukemia by constitutive activation of MADD/ERK and PIK3R2/AKT signaling pathways

• Published in: Oncotarget 2015-12, Vol.6 (42), p.44422-44436
• Main Authors: Wang, Lu Qian, Wong, Kwan Yeung, Rosèn, Anders, Chim, Chor Sang
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; Adult; Aged; Aged, 80 and over; Apoptosis; Asian Continental Ancestry Group - genetics; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Binding Sites; Cell Line, Tumor; Cell Proliferation; China; Death Domain Receptor Signaling Adaptor Proteins - genetics; Death Domain Receptor Signaling Adaptor Proteins - metabolism; DNA Methylation - drug effects; DNA Modification Methylases - antagonists & inhibitors; DNA Modification Methylases - metabolism; Enzyme Activation; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression Regulation, Neoplastic; Gene Silencing - drug effects; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; RNA Interference; Signal Transduction; Transfection
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6251

We hypothesize that miR-3151, localized to a GWAS-identified chronic lymphocytic leukemia (CLL) risk locus (8q22.3), is a tumor suppressor miRNA silenced by promoter DNA methylation in CLL. The promoter of miR-3151 was methylated in 5/7 (71%) CLL cell lines, 30/98 (31%) diagnostic primary samples, but not normal controls. Methylation of miR-3151 correlated inversely with expression. Treatment with 5-Aza-2'-deoxycytidine led to promoter demethylation and miR-3151 re-expression. Luciferase assay confirmed MAP-kinase activating death domain (MADD) and phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) as direct targets of miR-3151. Moreover, restoration of miR-3151 resulted in inhibition of cellular proliferation and enhanced apoptosis, repression of MADD and PIK3R2, downregulation of MEK/ERK and PI3K/AKT signaling, and repression of MCL1. Lastly, miR-3151 methylation was significantly associated with methylation of miR-203 and miR-34b/c in primary CLL samples. Therefore, this study showed that miR-3151 is a tumor suppressive miRNA frequently hypermethylated and hence silenced in CLL. miR-3151 silencing by DNA methylation protected CLL cells from apoptosis through over-expression of its direct targets MADD and PIK3R2, hence constitutive activation of MEK/ERK and PI3K/AKT signaling respectively, and consequently over-expression of MCL1.