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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

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 stud...

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Autores principales: Kurz, Lukas, Miklyaeva, Alissa, Skowron, Margaretha A., Overbeck, Nina, Poschmann, Gereon, Becker, Teresa, Eul, Katharina, Kurz, Thomas, Schönberger, Stefan, Calaminus, Gabriele, Stühler, Kai, Dykhuizen, Emily, Albers, Peter, Nettersheim, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226530/
https://www.ncbi.nlm.nih.gov/pubmed/32272809
http://dx.doi.org/10.3390/cancers12040905
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author Kurz, Lukas
Miklyaeva, Alissa
Skowron, Margaretha A.
Overbeck, Nina
Poschmann, Gereon
Becker, Teresa
Eul, Katharina
Kurz, Thomas
Schönberger, Stefan
Calaminus, Gabriele
Stühler, Kai
Dykhuizen, Emily
Albers, Peter
Nettersheim, Daniel
author_facet Kurz, Lukas
Miklyaeva, Alissa
Skowron, Margaretha A.
Overbeck, Nina
Poschmann, Gereon
Becker, Teresa
Eul, Katharina
Kurz, Thomas
Schönberger, Stefan
Calaminus, Gabriele
Stühler, Kai
Dykhuizen, Emily
Albers, Peter
Nettersheim, Daniel
author_sort Kurz, Lukas
collection PubMed
description 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.
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spelling pubmed-72265302020-05-18 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 Kurz, Lukas Miklyaeva, Alissa Skowron, Margaretha A. Overbeck, Nina Poschmann, Gereon Becker, Teresa Eul, Katharina Kurz, Thomas Schönberger, Stefan Calaminus, Gabriele Stühler, Kai Dykhuizen, Emily Albers, Peter Nettersheim, Daniel Cancers (Basel) Article 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. MDPI 2020-04-07 /pmc/articles/PMC7226530/ /pubmed/32272809 http://dx.doi.org/10.3390/cancers12040905 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kurz, Lukas
Miklyaeva, Alissa
Skowron, Margaretha A.
Overbeck, Nina
Poschmann, Gereon
Becker, Teresa
Eul, Katharina
Kurz, Thomas
Schönberger, Stefan
Calaminus, Gabriele
Stühler, Kai
Dykhuizen, Emily
Albers, Peter
Nettersheim, Daniel
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226530/
https://www.ncbi.nlm.nih.gov/pubmed/32272809
http://dx.doi.org/10.3390/cancers12040905
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