Transcriptional profiling of EHMT1/2 depletion and overexpression in various high grade serous ovarian cancer models
Euchromatin methyltransferase1/2 (EHMT1/2) have been correlated with tumorigenesis and therapy resistance through unknown mechanisms of action. Using a combination of experimental and bioinformatic analyses in several PARP inhibitor resistant ovarian cancer models, we demonstrate that combinatory EHMT and PARP inhibition is effective in treating PARP inhibitor resistant ovarian cancers. Our in vitro studies show that combinatory therapy reactivates transposable elements and increased immunostimulatory dsRNA formation and several immune signaling pathways. Our in vivo studies show that single EHMT and combinatory EHMT and PARP inhibition reduces tumor burden and that this reduction is dependent on CD8 T cells. Together, our results show a direct mechanism by which transposable elements are regulated and how an epigenetic therapy can be used as a fine tune agent to treat cancers with specific genetics. Overall design: Transcriptional profiling (RNA-seq) of patient-derived ex vivo tissues, PEO1-R, Kuramochi-R, OVCAR420-R, and ID8-R cells that were treated with DMSO, a PARP inhibitor (olaparib), an EHMT1/2 inhibitor (UNC0642 or EZM8266) or combinatory PARP/EHMT inhbitors. There is also a set of PEO1 cells with EHMT1 or EHMT2 overexpressed