Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model
Open Access
- 14 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 20 (1), 1-12
- https://doi.org/10.1186/s12885-020-06937-8
Abstract
Enhancer of zeste homolog 2 (EZH2) is considered an important driver of tumor development and progression by its histone modifying capabilities. Inhibition of EZH2 activity is thought to be a potent treatment option for eligible cancer patients with an aberrant EZH2 expression profile, thus the indirect EZH2 inhibitor 3-Deazaneplanocin A (DZNep) is currently under evaluation for its clinical utility. Although DZNep blocks proliferation and induces apoptosis in different tumor types including lymphomas, acquired resistance to DZNep may limit its clinical application. To investigate possible mechanisms of acquired DZNep resistance in B-cell lymphomas, we generated a DZNep-resistant clone from a previously DZNep-sensitive B-cell lymphoma cell line by long-term treatment with increasing concentrations of DZNep (ranging from 200 to 2000 nM) and compared the molecular profiles of resistant and wild-type clones. This comparison was done using molecular techniques such as flow cytometry, copy number variation assay (OncoScan and TaqMan assays), fluorescence in situ hybridization, Western blot, immunohistochemistry and metabolomics analysis. Whole exome sequencing did not indicate the acquisition of biologically meaningful single nucleotide variants. Analysis of copy number alterations, however, demonstrated among other acquired imbalances an amplification (about 30 times) of the S-adenosyl-L-homocysteine hydrolase (AHCY) gene in the resistant clone. AHCY is a direct target of DZNep and is critically involved in the biological methylation process, where it catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine to L-homocysteine and adenosine. The amplification of the AHCY gene is paralleled by strong overexpression of AHCY at both the transcriptional and protein level, and persists upon culturing the resistant clone in a DZNep-free medium. This study reveals one possible molecular mechanism how B-cell lymphomas can acquire resistance to DZNep, and proposes AHCY as a potential biomarker for investigation during the administration of EZH2-targeted therapy with DZNep.Keywords
This publication has 56 references indexed in Scilit:
- Acquired irinotecan resistance is accompanied by stable modifications of cell cycle dynamics independent of MSI statusInternational Journal of Oncology, 2013
- The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics DataCancer Discovery, 2012
- EZH2 Mediates Epigenetic Silencing of Neuroblastoma Suppressor Genes CASZ1, CLU, RUNX3, and NGFRCancer Research, 2012
- Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma CellsPLOS ONE, 2011
- Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancerMolecular Cancer, 2011
- Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cellsBlood, 2009
- DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylationMolecular Cancer Therapeutics, 2009
- Alterations of proliferative and differentiation potentials of human embryonic stem cells during long-term cultureExperimental & Molecular Medicine, 2008
- Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cellsGenes & Development, 2007
- Quantitative real-time PCR protocol for analysis of nuclear receptor signaling pathwaysNuclear Receptor Signaling, 2003