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Rewiring of cisplatin-resistant bladder cancer cells through epigenetic regulation of genes involved in amino acid metabolism
- Source :
- Theranostics
- Publication Year :
- 2018
- Publisher :
- Ivyspring International Publisher, 2018.
-
Abstract
- Alterations in DNA methylation are important epigenetic markers in bladder cancer (BC). These epigenome modifications may drive the mechanisms of aggressive chemo-resistant BC. Clinicopathological biomarkers that indicate chemotherapeutic resistance are critical for better assessing treatment strategies for individual patients. Thus, in this study, we aimed to determine whether DNA methylation of certain metabolic enzymes is significantly altered in cisplatin-resistant BC cells. Methods: To characterize CpG methylation and nucleosome accessibility in cisplatin-resistant BC cells, the Illumina Infinium HM450 DNA methylation assay was performed. Perturbed gene expression was found to be associated with cisplatin resistance, and the biological roles of spermidine/spermine N1-acetyltransferase (SAT1) and argininosuccinate synthase 1 (ASS1) were further studied using qRT-PCR analysis and various cell biology assays, including western blot. Results: ASS1 and SAT1, genes for amino acid and polyamine metabolism catalysts, respectively, were found to be vastly hypermethylated, resulting in greatly downregulated expression. ASS1 expression is of particular interest because prior studies have demonstrated its potential association with BC stage and recurrence. In regard to chemoresistance, we found that aberrant expression or induced stimulation of SAT1 restored cisplatin sensitivity in the cell culture system. We also found that the addition of exogenous arginine deiminase through administration of ADI-PEG 20 (pegylated arginine deiminase) increased ASS1 expression and enhanced cisplatin's apoptotic effects. Conclusions: Our study demonstrates a novel mechanistic link between the epigenetic perturbation of SAT1 and ASS1 and cancer metabolism in cisplatin-resistant bladder cancer cells. These findings suggest potential utility of SAT1 and ASS1 as predictive biomarkers in re-sensitizing bladder cancer to chemotherapy and personalizing therapy.
- Subjects :
- 0301 basic medicine
cancer metabolism
Medicine (miscellaneous)
Spermine
ASS1
Antineoplastic Agents
Argininosuccinate Synthase
Biology
SAT1
Real-Time Polymerase Chain Reaction
Epigenesis, Genetic
03 medical and health sciences
chemistry.chemical_compound
Acetyltransferases
Cell Line, Tumor
Gene expression
medicine
Humans
Epigenetics
Amino Acids
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Arginine deiminase
Cisplatin
DNA methylation
Bladder cancer
Gene Expression Profiling
Epigenome
medicine.disease
metabolomics
3. Good health
030104 developmental biology
Urinary Bladder Neoplasms
chemistry
chromatin accessibility
Drug Resistance, Neoplasm
Cancer research
cisplatin resistance
Metabolic Networks and Pathways
Research Paper
medicine.drug
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....ef93864eeca1d190aa9d30698f4ced1e
- Full Text :
- https://doi.org/10.7150/thno.25130