Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer

Irfan A. Asangani; Bushra Ateeq; Qi Cao; Lois Dodson; Mithil Pandhi; Lakshmi P. Kunju; Rohit Mehra; Robert J. Lonigro; Javed Siddiqui; Nallasivam Palanisamy; Yi Mi Wu; Xuhong Cao; Jung H. Kim; Meng Zhao; Zhaohui S. Qin; Mathew K. Iyer; Christopher A. Maher; Chandan Kumar-Sinha; Sooryanarayana Varambally; Arul M. Chinnaiyan

doi:10.1016/j.molcel.2012.10.008

Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer

Irfan A. Asangani, Bushra Ateeq, Qi Cao, Lois Dodson, Mithil Pandhi, Lakshmi P. Kunju, Rohit Mehra, Robert J. Lonigro, Javed Siddiqui, Nallasivam Palanisamy, Yi Mi Wu, Xuhong Cao, Jung H. Kim, Meng Zhao, Zhaohui S. Qin, Mathew K. Iyer, Christopher A. Maher, Chandan Kumar-Sinha, Sooryanarayana Varambally, Arul M. Chinnaiyan

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Abstract

Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.

Original language	English (US)
Pages (from-to)	80-93
Number of pages	14
Journal	Molecular Cell
Volume	49
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2012.10.008
State	Published - Jan 10 2013

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.10.008

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Asangani, I. A., Ateeq, B., Cao, Q., Dodson, L., Pandhi, M., Kunju, L. P., Mehra, R., Lonigro, R. J., Siddiqui, J., Palanisamy, N., Wu, Y. M., Cao, X., Kim, J. H., Zhao, M., Qin, Z. S., Iyer, M. K., Maher, C. A., Kumar-Sinha, C., Varambally, S., & Chinnaiyan, A. M. (2013). Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer. Molecular Cell, 49(1), 80-93. https://doi.org/10.1016/j.molcel.2012.10.008

Asangani, IA, Ateeq, B, Cao, Q, Dodson, L, Pandhi, M, Kunju, LP, Mehra, R, Lonigro, RJ, Siddiqui, J, Palanisamy, N, Wu, YM, Cao, X, Kim, JH, Zhao, M, Qin, ZS, Iyer, MK, Maher, CA, Kumar-Sinha, C, Varambally, S & Chinnaiyan, AM 2013, 'Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer', Molecular Cell, vol. 49, no. 1, pp. 80-93. https://doi.org/10.1016/j.molcel.2012.10.008

@article{8fd1d333b5a145d68b65cbc9df150f25,

title = "Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer",

abstract = "Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.",

author = "Asangani, {Irfan A.} and Bushra Ateeq and Qi Cao and Lois Dodson and Mithil Pandhi and Kunju, {Lakshmi P.} and Rohit Mehra and Lonigro, {Robert J.} and Javed Siddiqui and Nallasivam Palanisamy and Wu, {Yi Mi} and Xuhong Cao and Kim, {Jung H.} and Meng Zhao and Qin, {Zhaohui S.} and Iyer, {Mathew K.} and Maher, {Christopher A.} and Chandan Kumar-Sinha and Sooryanarayana Varambally and Chinnaiyan, {Arul M.}",

note = "Funding Information: We thank Catherine Grasso for RNA-seq portal, T. Barrette for database management, Vijaya Lakshmi Dommeti, Xiaojun Jing, and Khalid Suleman for technical assistance, Dashyant Dhanak, and Victor E. Marquez, NCI Center for Cancer Research, for providing DZNep, Caretha Creasy and Peter Tummino from GlaxoSmithKline for their lead EZH2 inhibitor compounds, and Jyoti Athanikar and Karen Giles for critical reading of the manuscript and submission of documents. This work was supported in part by grants from the Early Detection Research Network (UO1 CA111275), Prostate SPORE (P50CA69568), and the Department of Defense (DOD) Era of Hope (BC075023) to A.M.C. A.M.C. is also supported by the Doris Duke Charitable Foundation Clinical Scientist Award and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society Research Professor and A. Alfred Taubman Scholar. Q.C. is supported by a DOD postdoctoral training award (PC094725). Q.Z. is supported by the NIH (RO1HG005119). S.V. is supported by the NIH (R01CA157845). A.M.C. is a cofounder and SAB member of Compendia Biosciences, which supports Oncomine and the associated bioinformatics tools. A.M.C. serves on the SAB of Constellation Pharmaceuticals and serves as an advisor to Ventana/Roche and Glaxo Smith Kline. None of these companies were involved in these studies or approved of its content. I.A.A. and A.M.C. conceived the study and experiments. I.A.A. performed majority of the experiments with assistance from Q.C., L.D., M.P., and S.V. B.A performed mouse xenograft studies. L.P.K., R.M., R.J.L., J.S., and N.P. performed TMA staining and analysis. Y.-M.W. and X.C. constructed the ChIP-seq library and carried out sequencing. J.H.K., Z.M., and Z.S.Q performed ChIP-seq analysis. M.K.I and C.A.M. performed gene expression analysis and miRNA predictions. I.A.A, C.K.-S., and A.M.C wrote the manuscript, which was reviewed by all of the authors. ",

year = "2013",

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doi = "10.1016/j.molcel.2012.10.008",

language = "English (US)",

volume = "49",

pages = "80--93",

journal = "Molecular Cell",

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T1 - Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer

AU - Asangani, Irfan A.

AU - Ateeq, Bushra

AU - Cao, Qi

AU - Dodson, Lois

AU - Pandhi, Mithil

AU - Kunju, Lakshmi P.

AU - Mehra, Rohit

AU - Lonigro, Robert J.

AU - Siddiqui, Javed

AU - Palanisamy, Nallasivam

AU - Wu, Yi Mi

AU - Cao, Xuhong

AU - Kim, Jung H.

AU - Zhao, Meng

AU - Qin, Zhaohui S.

AU - Iyer, Mathew K.

AU - Maher, Christopher A.

AU - Kumar-Sinha, Chandan

AU - Varambally, Sooryanarayana

AU - Chinnaiyan, Arul M.

N1 - Funding Information: We thank Catherine Grasso for RNA-seq portal, T. Barrette for database management, Vijaya Lakshmi Dommeti, Xiaojun Jing, and Khalid Suleman for technical assistance, Dashyant Dhanak, and Victor E. Marquez, NCI Center for Cancer Research, for providing DZNep, Caretha Creasy and Peter Tummino from GlaxoSmithKline for their lead EZH2 inhibitor compounds, and Jyoti Athanikar and Karen Giles for critical reading of the manuscript and submission of documents. This work was supported in part by grants from the Early Detection Research Network (UO1 CA111275), Prostate SPORE (P50CA69568), and the Department of Defense (DOD) Era of Hope (BC075023) to A.M.C. A.M.C. is also supported by the Doris Duke Charitable Foundation Clinical Scientist Award and the Prostate Cancer Foundation. A.M.C. is an American Cancer Society Research Professor and A. Alfred Taubman Scholar. Q.C. is supported by a DOD postdoctoral training award (PC094725). Q.Z. is supported by the NIH (RO1HG005119). S.V. is supported by the NIH (R01CA157845). A.M.C. is a cofounder and SAB member of Compendia Biosciences, which supports Oncomine and the associated bioinformatics tools. A.M.C. serves on the SAB of Constellation Pharmaceuticals and serves as an advisor to Ventana/Roche and Glaxo Smith Kline. None of these companies were involved in these studies or approved of its content. I.A.A. and A.M.C. conceived the study and experiments. I.A.A. performed majority of the experiments with assistance from Q.C., L.D., M.P., and S.V. B.A performed mouse xenograft studies. L.P.K., R.M., R.J.L., J.S., and N.P. performed TMA staining and analysis. Y.-M.W. and X.C. constructed the ChIP-seq library and carried out sequencing. J.H.K., Z.M., and Z.S.Q performed ChIP-seq analysis. M.K.I and C.A.M. performed gene expression analysis and miRNA predictions. I.A.A, C.K.-S., and A.M.C wrote the manuscript, which was reviewed by all of the authors.

PY - 2013/1/10

Y1 - 2013/1/10

N2 - Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.

AB - Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.

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ER -

Characterization of the EZH2-MMSET Histone Methyltransferase Regulatory Axis in Cancer

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