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Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors
Purpose Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of ge...
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Published in: | Journal of neuro-oncology 2019-01, Vol.141 (1), p.43-55 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Purpose
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.
Methods
The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a
Drosophila melanogaster
model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.
Results
Knockdown of
Snr1
, the fly orthologue of
SMARCB1
, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g.
CG10348
, the fly orthologue of transcriptional regulator
PRDM16
. Subsequently,
PRDM16
was found to be over-expressed in ATRT samples and knockdown of
PRDM16
in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.
Conclusions
These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT. |
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ISSN: | 0167-594X 1573-7373 |
DOI: | 10.1007/s11060-018-03018-6 |