Epigenetic silencing of the proapoptotic gene BIM in anaplastic large cell lymphoma through an MeCP2/SIN3a deacetylating complex
Open accessAbstract
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 BIM epigenetic silencing but is able to act as an inducer of BIM methylation.
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HDAC1/2 multiprotein complexes can also repress the expression of pro-apoptotic genes.
“Focusing on a single target gene could lead to misinterpretation, as HDAC1/2 multiprotein complexes can also repress the expression of pro-apoptotic genes (Contreras et al., 2013;Piazza et al., 2013;Ramsey, He, Forster, Ory, & Ellisen, 2011).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Piazza et al., 2013
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References 53 · Cited by 51
- Authors
- Piazza, R., Magistroni, V., Mogavero, A., Andreoni, F., Ambrogio, C., Chiarle, R., Mologni, L., Bachmann, P. S., Lock, R. B., Collini, P., Pelosi, G., & Gambacorti-Passerini, C.
- Affiliations
- University of Milan (IT)
- University of Turin (IT)
- UNSW Sydney (AU)
- Corresponding author
- Piazza, Rocco
- ORCID
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 15
- Issue
- 5
- Pages
- 511-IN17
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC3638354
- OpenAlex
- W1801993810
- Cited by
- 51
- References
- 53
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 11 · 2016: 4 · 2015: 11 · 2014: 1 · 2013: 1
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- BOA (University of Milano-Bicocca) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- Fondazione Cariplo (2009-2667)
- Associazione Italiana per la Ricerca sul Cancro (IG-10092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- building information modeling, anaplastic large cell lymphoma, NPM-ALK, epigenetic silencing, MeCP2, SIN3A, histone acetylation, DNA methylation, CpG methylation, trichostatin A, azacitidine, apoptosis, Bcl-2 family proteins, ALK inhibitors, histone deacetylase inhibitors
- MeSH terms
- Bcl-2-Like Protein 11, Acetylation, Cell Survival, Chromatin, Histones, Humans, Hydroxamic Acids, Membrane Proteins, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Repressor Proteins, Gene Expression Regulation, Neoplastic, Case-Control Studies, Lymphoma, Large-Cell, Anaplastic, CpG Islands, DNA Methylation, 5' Untranslated Regions, Gene Silencing, Epigenesis, Genetic, Cell Line, Tumor, Apoptosis Regulatory Proteins, Methyl-CpG-Binding Protein 2, Sin3 Histone Deacetylase and Corepressor Complex, Histone Deacetylase Inhibitors
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