Format

Send to

Choose Destination
Cancer Cell. 2012 Oct 16;22(4):506-523. doi: 10.1016/j.ccr.2012.09.003.

Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.

Author information

1
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
2
Department of Immunology and Malignant Hematology, Tianjin Cancer Hospital, Tianjin, China.
3
Experimental Therapeutics, University of Kansas Cancer Center, Kansas City, Kansas 66160.
4
Dana-Farber Cancer Institute, Boston, MA 02115.
5
Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198.
6
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
7
Department of Pathology, Weill-Cornell Medical College, New York, NY 10065.
#
Contributed equally

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.

PMID:
23079660
PMCID:
PMC3973134
DOI:
10.1016/j.ccr.2012.09.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center