Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes [ChIP-Seq]

The combination of epigenetic and immunotherapy is emerging as a promising approach for cancer therapy. Derepression of transposable elements (TE) by epigenetic drugs leads to activation of immune response. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) in context of p53 is still elusive. Here, we used FDA-approved epigenetic drugs to systematically inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal, esophageal, and prostate cancer cells. We show that distinct TE subfamilies are derepressed by inhibition of different CMEs in cell type-specific manner. Co-inhibition of DNMT and HDAC (DNMTi-HDACi) had the most consistent effect across cancer types. Loss of p53 results in stronger TE activation and TE-chimeric transcript expression and this effect is largely mediated by the non-genomic actions of p53. Robust immune response elicited by DNMTi-HDACi is due to induced inverted repeat Alu expression concomitant with reduced ADAR1-mediated Alu RNA editing, whereas SETDB1 inhibition activates ADAR1 expression. Collectively, our systematic analyses provide insights for rational use of epigenetic therapies in distinct cancers. Transcription factor binding was determined by ChIP-seq in GP5d and OE19 cells. Gene expression profiling for GP5d, OE19, LNCAP-1FP, GP5d p53-KO and LNCAP-1Fo p53-KO cells (DMSO treated, DNMT inhibited, HDAC inhibited, SETDB1 inhibited and DNMT-HDAC co-inhibited, DNMT-SETDB1 co-inhibited, HDAC-SETDB1 co-inhibited) was performed by RNA-seq.