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

Abstract

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.

Loss of ARID1A Expression as a Favorable Prognostic Factor in Early-Stage Grade 3 Endometrioid Endometrial Carcinoma Patients

“…However, most cases with ARID1A loss do not seem to have a co-existing POLE mutation. Recently, POLE has been reported as one of the putative downstream effectors of ARID1A [ 28 ]. In line with this, ARID1A-mutant tumors have been consistently reported as having higher mutation load than that of ARID1A-intact tumors [ 15 , 27 ].…”

The signal transducer CD24 suppresses the germ cell program and promotes an ectodermal rather than mesodermal cell fate in embryonal carcinomas

“…Utilized antibodies are listed in table S3 (Table S3). Cell cycle analysis and apoptosis assay using PI or PI/Annexin V staining, respectively, with subsequent flow cytometric analysis have been performed as described previously [49].…”

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

“…Similarly, in germ cell tumors, ARID1A deficiency produced by CRISPR/Cas9 gene editing or pharmacological inhibition considerably sensitized tumor cells towards ATR inhibition ( 129 ). Mechanistically, ARID1A was postulated to control gene transcription, DDR, and epigenetic profile through putative downstream effectors DNA methyltransferase 1-associated protein DMAP1 and DNA Polymerase POLE.…”