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Epigenetic Silencing of the Proapoptotic Gene BIM in Anaplastic Large Cell Lymphoma through an MeCP2/SIN3a Deacetylating Complex.
- Source :
-
Neoplasia . May2013, Vol. 15 Issue 5, p511-522. 14p. - Publication Year :
- 2013
-
Abstract
- BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIMepigenetic silencing but is able to act as an inducer of BIM methylation. [ABSTRACT FROM AUTHOR]
- Subjects :
- *EPIGENESIS
*GENE silencing
*DEACETYLATION
*LYMPHOMAS
*CANCER cells
Subjects
Details
- Language :
- English
- ISSN :
- 15228002
- Volume :
- 15
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Neoplasia
- Publication Type :
- Academic Journal
- Accession number :
- 88400326
- Full Text :
- https://doi.org/10.1593/neo.121784