Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas.
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.
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.|Department of Immunology and Malignant Hematology, Tianjin Cancer Hospital, Tianjin, China.
Xinwei
X
Zhang
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Xiaohong
X
Zhao
Experimental Therapeutics, University of Kansas Cancer Center, Kansas City, Kansas 66160.
Warren
W
Fiskus
Dana-Farber Cancer Institute, Boston, MA 02115.
Jianhong
J
Lin
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Tint
T
Lwin
Experimental Therapeutics, University of Kansas Cancer Center, Kansas City, Kansas 66160.
Rekha
R
Rao
Department of Immunology and Malignant Hematology, Tianjin Cancer Hospital, Tianjin, China.
Yizhuo
Y
Zhang
Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198.
John C
JC
Chan
Department of Pathology, University of Nebraska Medical Center, Omaha, NE 68198.
Kai
K
Fu
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.
Victor E
VE
Marquez
Department of Pathology, Weill-Cornell Medical College, New York, NY 10065.
Selina
S
Chen-Kiang
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Lynn C
LC
Moscinski
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Edward
E
Seto
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
William S
WS
Dalton
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Kenneth L
KL
Wright
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Eduardo
E
Sotomayor
Experimental Therapeutics, University of Kansas Cancer Center, Kansas City, Kansas 66160.
Kapil
K
Bhalla
Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Jianguo
J
Tao
D000818:Animals; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000235:genetics / Q000628:therapy; D008745:Methylation; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D000099186:Histone Deacetylase 3
D000071221:Enhancer of Zeste Homolog 2 Protein; D006655:Histone Deacetylases; D006657:Histones; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; D016271:Proto-Oncogene Proteins c-myc; D000099186:Histone Deacetylase 3; C528163:MIRN26 microRNA, human; C532045:MIRN29a microRNA, human; C547168:MIRN494 microRNA, human; C489427:MYC protein, human; C498409:EZH2 protein, human