Coordinated Silencing of MYC-mediated MiR-29 by HDAC3 and EZH2 As a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2012 Oct 20

PMID 23079660

Citations 164

Authors

Xinwei Zhang

Xiaohong Zhao

Warren Fiskus

Jianhong Lin

Tint Lwin

Rekha Rao

Yizhuo Zhang

John C Chan

Kai Fu

Victor E Marquez

Selina Chen-Kiang

Lynn C Moscinski

Edward Seto

William S Dalton

Kenneth L Wright

Eduardo Sotomayor

Kapil Bhalla

Jianguo Tao

Affiliations

Soon will be listed here.

Abstract

We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.

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