Transcriptional regulation of human endogenous retroviruses in cancer

Human endogenous retroviruses (HERVs) provide a direct record of the millions of years of co-evolution between humans and viruses. Yet, due to their repetitive nature and former reputation as "junk DNA," a full characterization of the functional roles and transcriptional regulation of HERVs remains to be achieved. As sequencing technologies improve, better resolution data regarding HERV expression and regulation has become attainable, and there is mounting evidence of aberrant HERV expression in various human diseases, particularly cancer. However, the perturbations to the transcriptional regulatory processes that govern these endogenized retroviral elements in cancer remain unclear. In this review, we will summarize the state of our understanding of the various mechanisms that control HERV expression in cancer, focusing primarily on aberrant methylation and KRAB-domain containing zinc finger proteins (KZFPs), among others. Many of these regulatory mechanisms are employed in stem cells to regulate pluripotency and differentiation and are also deployed in a subpopulation of cancer cells with high self-renewal and proliferation capacity, called cancer stem cells. While the expression of specific HERVs in cancer could be beneficial, deleterious, or neutral, the potential to use HERVs as biomarkers or immune adjuvants to enhance immunotherapies against cancer is promising. The implications of shared transcriptional mechanisms across cancer and stem cells will expose new areas to intervene with cancer treatments, ushering in a new era of HERV-based cancer therapeutics and diagnostics.