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

172 Citations (Scopus)

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

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Histone Code
B-Cell Lymphoma
Epigenetic Repression
Lymphoma
Mantle-Cell Lymphoma
Co-Repressor Proteins
MicroRNAs
B-Lymphocytes
Up-Regulation
Down-Regulation
Therapeutics
Growth
Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas. / Zhang, Xinwei; Zhao, Xiaohong; Fiskus, Warren; Lin, Jianhong; Lwin, Tint; Rao, Rekha; Zhang, Yizhuo; Chan, John C.; Fu, Kai; Marquez, Victor E.; Chen-Kiang, Selina; Moscinski, Lynn C.; Seto, Edward; Dalton, William S.; Wright, Kenneth L.; Sotomayor, Eduardo; Bhalla, Kapil; Tao, Jianguo.

In: Cancer Cell, Vol. 22, No. 4, 16.10.2012, p. 506-523.

Research output: Contribution to journalArticle

Zhang, X, Zhao, X, Fiskus, W, Lin, J, Lwin, T, Rao, R, Zhang, Y, Chan, JC, Fu, K, Marquez, VE, Chen-Kiang, S, Moscinski, LC, Seto, E, Dalton, WS, Wright, KL, 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, vol. 22, no. 4, pp. 506-523. https://doi.org/10.1016/j.ccr.2012.09.003
Zhang, Xinwei ; Zhao, Xiaohong ; Fiskus, Warren ; Lin, Jianhong ; Lwin, Tint ; Rao, Rekha ; Zhang, Yizhuo ; Chan, John C. ; Fu, Kai ; Marquez, Victor E. ; Chen-Kiang, Selina ; Moscinski, Lynn C. ; Seto, Edward ; Dalton, William S. ; Wright, Kenneth L. ; Sotomayor, Eduardo ; Bhalla, Kapil ; Tao, Jianguo. / Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas. In: Cancer Cell. 2012 ; Vol. 22, No. 4. pp. 506-523.
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AU - Lin, Jianhong

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AU - Rao, Rekha

AU - Zhang, Yizhuo

AU - Chan, John C.

AU - Fu, Kai

AU - Marquez, Victor E.

AU - Chen-Kiang, Selina

AU - Moscinski, Lynn C.

AU - Seto, Edward

AU - Dalton, William S.

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AU - Bhalla, Kapil

AU - Tao, Jianguo

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