Akpa, Chidimma Agatha and Kleo, Karsten and Oker, Elisabeth and Tomaszewski, Nancy and Messerschmidt, Clemens and Lopez, Cristina and Wagener, Rabea and Oehl-Huber, Kathrin and Dettmer, Katja and Schoeler, Anne and Lenze, Dido and Oefner, Peter J. and Beule, Dieter and Siebert, Reiner and Capper, David and Dimitrova, Lora and Hummel, Michael (2020) Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model. BMC CANCER, 20 (1). ISSN , 1471-2407
Full text not available from this repository. (Request a copy)Abstract
BackgroundEnhancer 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.MethodsTo 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 2000nM) 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.ResultsWhole 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.ConclusionsThis 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | COMBINED EPIGENETIC THERAPY; HISTONE METHYLATION; INHIBITOR 3-DEAZANEPLANOCIN; SUPPRESSOR GENES; DRUG-RESISTANCE; TARGETING EZH2; CANCER-CELLS; MECHANISMS; EXPRESSION; IDENTIFICATION; 3-Deazaneplanocin a (DZNep); B-cell lymphoma; Enhancer of zeste homolog 2 (EZH2); S-adenosyl-L-homocysteine hydrolase (AHCY) |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2021 07:46 |
| Last Modified: | 24 Mar 2021 07:46 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44565 |
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