ARID1A Regulates Transcription and the Epigenetic Landscape via POLE and DMAP1 While ARID1A Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition
| Autor: | Thomas Kurz, Stefan Schönberger, Margaretha A. Skowron, Kai Stühler, Gereon Poschmann, Emily C. Dykhuizen, Gabriele Calaminus, Alissa Miklyaeva, Nina Overbeck, Lukas Kurz, Peter Albers, Teresa K. Becker, Katharina Eul, Daniel Nettersheim |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research ARID1A medicine.drug_class DNA repair Synthetic lethality Biology HDAC inhibition lcsh:RC254-282 ATR inhibition Article Romidepsin 03 medical and health sciences 0302 clinical medicine medicine Epigenetics germ cell tumors CRISPR/Cas9 mass spectrometry Cisplatin Histone deacetylase inhibitor EZH2 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research SWI/SNF-complex molecular therapy medicine.drug |
| Zdroj: | Cancers Volume 12 Issue 4 Cancers, Vol 12, Iss 905, p 905 (2020) |
| ISSN: | 2072-6694 |
| Popis: | Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate by mass spectrometry that ARID1A is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A/ARID1A deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs. |
| Databáze: | OpenAIRE |
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