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A key role for EZH2...
A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
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- Kanduri, Meena, 1974 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
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- Sander, Birgitta (author)
- Karolinska Institutet
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Ntoufa, Stavroula (author)
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Papakonstantinou, Nikos (author)
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- Sutton, Lesley-Ann (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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Stamatopoulos, Kostas (author)
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- Kanduri, Chandrasekhar, 1967 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik,Institute of Biomedicine, Department of Medical and Clinical Genetics
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- Rosenquist, Richard (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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(creator_code:org_t)
- 2014-10-27
- 2013
- English.
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In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:12, s. 1280-8
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Abstract
Subject headings
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- The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- DNA methylation
- EZH2
- HOX genes
- chronic lymphocytic leukemia
- histone methylation
- mantle cell lymphoma
Publication and Content Type
- ref (subject category)
- art (subject category)
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