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

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

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 journal › Article › peer-review

240 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 language	English (US)
Pages (from-to)	506-523
Number of pages	18
Journal	Cancer Cell
Volume	22
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2012.09.003
State	Published - Oct 16 2012
Externally published	Yes

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

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

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

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.",

author = "Xinwei Zhang and Xiaohong Zhao and Warren Fiskus and Jianhong Lin and Tint Lwin and Rekha Rao and Yizhuo Zhang and Chan, {John C.} and Kai Fu and Marquez, {Victor E.} and Selina Chen-Kiang and Moscinski, {Lynn C.} and Edward Seto and Dalton, {William S.} and Wright, {Kenneth L.} and Eduardo Sotomayor and Kapil Bhalla and Jianguo Tao",

note = "Funding Information: We are grateful to the Tissue Procurement and Molecular Core Laboratory at Moffitt Cancer Center for providing specimens and molecular analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institute (Grant R01 CA137123 to J.T.), the Maher Fund (to J.T.), the Susan and John Sykes Lymphoma Research Fund (to J.T.) and the Lymphoma Research Foundation (to J.T.). ",

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doi = "10.1016/j.ccr.2012.09.003",

language = "English (US)",

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T1 - Coordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell Lymphomas

AU - Zhang, Xinwei

AU - Zhao, Xiaohong

AU - Fiskus, Warren

AU - Lin, Jianhong

AU - Lwin, Tint

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.

AU - Wright, Kenneth L.

AU - Sotomayor, Eduardo

AU - Bhalla, Kapil

AU - Tao, Jianguo

N1 - Funding Information: We are grateful to the Tissue Procurement and Molecular Core Laboratory at Moffitt Cancer Center for providing specimens and molecular analysis. We thank Rasa Hamilton for editorial assistance. This work was supported by grants from the National Cancer Institute (Grant R01 CA137123 to J.T.), the Maher Fund (to J.T.), the Susan and John Sykes Lymphoma Research Fund (to J.T.) and the Lymphoma Research Foundation (to J.T.).

PY - 2012/10/16

Y1 - 2012/10/16

N2 - 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.

AB - 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.

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

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