Activation of oncogenic pathways in classical Hodgkin lymphoma by decitabine: A rationale for combination with small molecular weight inhibitors
| Autor: | Alexey Ushmorov, Thomas Wirth, T Swerev |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Cell Survival Decitabine Biology Epigenesis Genetic Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor medicine Humans Epigenetics B-cell lymphoma Cell Proliferation Oligonucleotide Array Sequence Analysis Gene Expression Profiling Oncogenes Cell cycle DNA Methylation medicine.disease Hodgkin Disease Demethylating agent Gene Expression Regulation Neoplastic 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis DNA methylation Cancer research Azacitidine Epigenetic therapy medicine.drug Signal Transduction |
| Zdroj: | International journal of oncology. 50(2) |
| ISSN: | 1791-2423 |
| Popis: | DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities. Although efficacy of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side‑effect of the demethylating agent 5‑azacytidine in a patient with myelodysplastic syndrome. We investigated molecular mechanisms of decitabine (5‑Aza‑dC) antitumor activity in cHL using gene expression profiling followed by gene set enrichment analysis. We found that 5‑Aza‑dC inhibits growth of cHL cell lines at clinically relevant concentrations of 0.25‑2 µM. The antitumor effect of 5‑Aza‑dC was associated with induction of genes, which negatively regulate cell cycle progression (e.g. CDKN1A and GADD45A). Surprisingly, we also observed significant enrichment of pro‑survival pathways like MEK/ERK, JAK‑STAT and NF‑κB, as well as signatures comprising transcription‑activating genes. Among the upregulated pro‑survival genes were the anti‑apoptotic genes BCL2 and BCL2L1, as well as genes involved in transduction of growth and survival signals like STAT1, TLR7, CD40 and IL-6. We therefore analyzed whether interference with these pro‑survival pathways and genes would potentiate the antitumor effect of 5‑Aza‑dC. We could show that the BCL2/BCL2L1 inhibitor ABT263, the JAK‑STAT inhibitors fedratinib and SH‑4‑54, the AKT inhibitor KP372‑1, the NF‑κB inhibitor QNZ, as well as the bromodomain and extraterminal (BET) family proteins inhibitor JQ1 acted synergistically with 5‑Aza‑dC. We conclude that targeting of oncogenic pathways of cHL may improve efficacy of DNA-demethylating therapy in cHL. |
| Databáze: | OpenAIRE |
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