Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma.
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.
Berdasco
María
M
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, 08907 L'Hospitalet, Spain.
Ropero
Santiago
S
Setien
Fernando
F
Fraga
Mario F
MF
Lapunzina
Pablo
P
Losson
Régine
R
Alaminos
Miguel
M
Cheung
Nai-Kong
NK
Rahman
Nazneen
N
Esteller
Manel
M
D000015:Abnormalities, Multiple / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005910:Glioma / Q000201:enzymology* / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic; D013577:Syndrome
D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase