Abstract
Epigenetics, c-Myc and Aggressive B-cell Lymphomas
Highlights
We revealed 1) loss or low expression of c-Myc-regulated miRNAs in aggressive B-cell lymphomas; 2) reverse correlation of tumor suppressor miRNAs such as miR26a and miR29-a-c with Myc as well as cell proliferation, CDK6, and IGF-1R expression; 3) ectopic expression of miR-26a, miR-29 suppression of CDK-6, and IGF-1R and Myc-driven cell proliferation in aggressive lymphoma cell lines and primary lymphomas; and 4) miR-26a and miR-29 repression as a result of Myc/HDAC3 and EZH2 interaction
Results of these studies have led to the identification of a novel model for interplay between Myc, HDAC3, PRC2, and miRNAs and their contribution to Myc-associated lymphomagenesis, and HDAC3/EZH2/miRNAs as novel therapeutic targets
Our study showed that treatment with the pan-HDAC inhibitor SAHA, the EZH2 inhibitor DZNep, and their specific siRNAs disrupted Myc hyperactivity, resulting in enhanced restoration of miR-29a-c expression, downregulation of miR-29 targeting genes CDK6 and IGF-1R, and suppression of lymphoma cell growth ex vivo and in vivo
Summary
Results of these studies have led to the identification of a novel model for interplay between Myc, HDAC3, PRC2, and miRNAs and their contribution to Myc-associated lymphomagenesis, and HDAC3/EZH2/miRNAs as novel therapeutic targets. HDCA3, and PRC2 form a repressive complex tethered to miR-29a/b1 and miR-29b2/c promoter regulatory elements to epigenetically repress transcription of these miRNAs in Myc-expressing lymphoma cells and that subsequent miR-29 down-regulation results in induction of oncogenic proteins (CDK6 and IGF-1R) and Myc-driven lymphomagenesis.
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