HERVs New Role in Cancer: From Accused Perpetrators to Cheerful Protectors

Abstract

Initial indications that retroviruses are connected to neoplastic transformation were seen more than a century ago. This concept has also been tested for endogenized retroviruses (ERVs) that are abundantly expressed in many transformed cells. In healthy cells, ERV expression is commonly prevented by DNA methylation and other epigenetic control mechanisms. ERVs are remnants of former exogenous forms that invaded the germ line of the host and have since been vertically transmitted. Several examples of ERV-induced genomic recombination events and dysregulation of cellular genes that contribute to tumor formation have been well documented. Moreover, evidence is accumulating that certain ERV proteins have oncogenic properties. In contrast to these implications for supporting cancer induction, a recent string of papers has described favorable outcomes of increasing human ERV (HERV) RNA and DNA abundance by treatment of cancer cells with methyltransferase inhibitors. Analogous to an infecting agent, the ERV-derived nucleic acids are sensed in the cytoplasm and activate innate immune responses that drive the tumor cell into apoptosis. This "viral mimicry" induced by epigenetic drugs might offer novel therapeutic approaches to help target cancer cells that are normally difficult to treat using standard chemotherapy. In this review, we discuss both the detrimental and the new beneficial role of HERV reactivation in terms of its implications for cancer.

Keywords: DNA-methylation; HERV; HERV-K; cancer; human endogenous retrovirus (HERV); innate sensing; viral mimicry.

FIGURE 1

Genomic organization of HERV-K(HML-2) and proposed role of HERVs in tumorigenesis. (A) Schematic depiction of the HERV-K(HML-2) provirus. (B) Presumed cancer promoting implications of HERVs at the DNA level. (i) Recombination event leading to an LTR-driven expression of exons of a potential oncogene. (ii) LTR-driven expression of a nearby proto-oncogene. Exons are shown in green and the cellular promotor in blue. (C) Potential cancer-promoting effects by HERV-encoded proteins Env (i) and Rec/Np9 (ii). Aberrant signal transduction leading to transformation of the cell is indicated by a lightning sign. Binding of Rec or Np9 to PLZF prevents PLZF from functionally inhibiting c-MYC. Interaction of Rec with TZFP or hSGT has been suggested to abrogate inhibition of the androgen receptor by these two cellular proteins. Interaction of Np9 with LNX activates the LNX/Numb/Notch pathway.

FIGURE 2

Antitumor activity mediated by innate sensing of HERV RNA and DNA. Treatment of cancer cells with DNMTis results in demethylation of the LTR promotors and HERV transcription. Viral nucleic acids in the cytoplasm and other cellular compartments (viral mimicry) are sensed by TLRs and other innate sensors including MDA5. Upon activation these pattern recognition receptors initiate signal transduction pathways that result in production of type I and III IFNs and pro-inflammatory cytokines further leading to promotion of an adaptive immune response (e.g., anti-HERV antibodies).