Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

Authors

• Xinwei Zhang, Tianjin Cancer Hospital
• Xiaohong Zhao, H. Lee Moffitt Cancer Center and Research Institute
• Warren Fiskus, University of Kansas Cancer Center
• Jianhong Lin, Dana-Farber Cancer Institute
• Tint Lwin, H. Lee Moffitt Cancer Center and Research Institute
• Rekha Rao, University of Kansas Cancer Center
• Yizhuo Zhang, Tianjin Cancer Hospital
• John C. Chan, University of Nebraska Medical Center
• Kai Fu, University of Nebraska Medical Center
• Victor E. Marquez, National Cancer Institute
• Selina Chen-Kiang, Weill-Cornell Medical College
• Lynn C. Moscinski, H. Lee Moffitt Cancer Center and Research Institute
• Edward Seto, H. Lee Moffitt Cancer Center and Research Institute
• William S. Dalton, H. Lee Moffitt Cancer Center and Research Institute
• Kenneth L. Wright, H. Lee Moffitt Cancer Center and Research Institute
• Eduardo Sotomayor, H. Lee Moffitt Cancer Center and Research Institute
• Kapil Bhalla, University of Kansas Cancer Center
• Jianguo Tao, H. Lee Moffitt Cancer Center and Research InstituteFollow

Date of this Version

2012

Citation

Published in Cancer Cell (2012) 22, 506–523. DOI: 10.1016/j.ccr.2012.09.003

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.