| Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma. | |
| | |
MedLine Citation:
|
PMID: 20018718 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Sotos syndrome is an autosomal dominant condition characterized by overgrowth resulting in tall stature and macrocephaly, together with an increased risk of tumorigenesis. The disease is caused by loss-of-function mutations and deletions of the nuclear receptor SET domain containing protein-1 (NSD1) gene, which encodes a histone methyltransferase involved in chromatin regulation. However, despite its causal role in Sotos syndrome and the typical accelerated growth of these patients, little is known about the putative contribution of NSD1 to human sporadic malignancies. Here, we report that NSD1 function is abrogated in human neuroblastoma and glioma cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also demonstrate that the epigenetic inactivation of NSD1 in transformed cells leads to the specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. The described phenotype is also observed in Sotos syndrome patients with NSD1 genetic disruption. Expression microarray data from NSD1-depleted cells, followed by ChIP analysis, revealed that the oncogene MEIS1 is one of the main NSD1 targets in neuroblastoma. Furthermore, we show that the restoration of NSD1 expression induces tumor suppressor-like features, such as reduced colony formation density and inhibition of cellular growth. Screening a large collection of different tumor types revealed that NSD1 CpG island hypermethylation was a common event in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation was a predictor of poor outcome in high-risk neuroblastoma. These findings highlight the importance of NSD1 epigenetic inactivation in neuroblastoma and glioma that leads to a disrupted histone methylation landscape and might have a translational value as a prognostic marker. |
| | |
Authors:
|
María Berdasco; Santiago Ropero; Fernando Setien; Mario F Fraga; Pablo Lapunzina; Régine Losson; Miguel Alaminos; Nai-Kong Cheung; Nazneen Rahman; Manel Esteller |
Related Documents
:
|
18763178 - A novel splice site mutation in the eya1 gene in a korean family with branchio-oto (bo)... 9605588 - Fgfr2 mutation associated with clinical manifestations consistent with antley-bixler sy... 17509468 - Nonclassic neurologic features in cryopyrin-associated periodic syndromes. 20303308 - Gonadal mosaicism of a taz (g4.5) mutation in a japanese family with barth syndrome and... 7055998 - A study of the inheritance pattern of romano-ward syndrome. prolonged q-t interval, syn... 11729598 - The prevention of shaken baby syndrome. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-14 |
Journal Detail:
|
Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 106 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2009 Dec |
Date Detail:
|
Created Date: 2010-01-18 Completed Date: 2010-02-18 Revised Date: 2010-09-28 |
Medline Journal Info:
|
Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
|
Languages: eng Pagination: 21830-5 Citation Subset: IM |
Affiliation:
|
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08907 L'Hospitalet, Spain. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Abnormalities, Multiple
/
genetics* Chromatin Immunoprecipitation CpG Islands DNA Methylation Epigenesis, Genetic* Glioma / enzymology*, genetics Growth Disorders / genetics* Histone-Lysine N-Methyltransferase / genetics* Humans Neuroblastoma / enzymology*, genetics Promoter Regions, Genetic Syndrome |
| Chemical | |
Reg. No./Substance:
|
EC 2.1.1.-/histone methyltransferase; EC 2.1.1.43/Histone-Lysine N-Methyltransferase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem...
Next Document: Functionality of the voltage-gated proton channel truncated in S4.