Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes

Abstract

The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.