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

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

Research output: Contribution to journalArticle

189 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)506-523
Number of pages18
JournalCancer Cell
Volume22
Issue number4
DOIs
StatePublished - Oct 16 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Zhang, X., Zhao, X., Fiskus, W., Lin, J., Lwin, T., Rao, R., Zhang, Y., Chan, J. C., Fu, K., Marquez, V. E., Chen-Kiang, S., Moscinski, L. C., Seto, E., Dalton, W. S., Wright, K. L., Sotomayor, E., Bhalla, K., & Tao, J. (2012). Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas. Cancer Cell, 22(4), 506-523. https://doi.org/10.1016/j.ccr.2012.09.003