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.

Three Poliovirus Sequences in the Human Genome Associated With Colorectal Cancer

“…Some HERV sequences have oncogenic properties; yet treating cancer cells with methyltransferase inhibitors increases HERV RNA and DNA. Like infectious agents, the HERV-derived nucleic acids in the cytoplasm activate innate immune responses that produce tumor cell apoptosis (11,12).…”

Evolutionary Medicine of Retroviruses in the Human Genome

“…32 HERV activation has also been reported in breast cancer, lymphoma, melanoma, ovarian cancer and prostate cancer, and the expression of env proteins can be involved in tumorigenesis via inducing cell-cell fusion. 33 In addition, it is known that sequences derived from HERVs can be a trigger of cancers if partial sequences of HERVs or HERV itself translocates to regulatory regions of oncogenes. 33 Tomlins et al reported that a translocation of HERV-K upstream of ETS translocation variant 1 caused cancerogenesis via enhanced expression of ETS translocation variant 1.…”

“…33 In addition, it is known that sequences derived from HERVs can be a trigger of cancers if partial sequences of HERVs or HERV itself translocates to regulatory regions of oncogenes. 33 Tomlins et al reported that a translocation of HERV-K upstream of ETS translocation variant 1 caused cancerogenesis via enhanced expression of ETS translocation variant 1. 34 HERV-K env genes originate 2 proteins (np9 and rec) with a different length by alternative splicing, and np9 proteins present 292bp deletion but rec is not ( Figure 1B).…”

The Decrease in Human Endogenous Retrovirus-H Activity Runs in Parallel with Improvement in ADHD Symptoms in Patients Undergoing Methylphenidate Therapy

“…HERVs have been mainly taken into account for their role in the molecular evolution of genomes [ 14 ]. However, in the last decades, several studies have underlined their involvement in the etiopathogenesis of complex diseases, such as cancer [ 15 , 16 ], autoimmune diseases [ 17 ], type 1 diabetes [ 18 ], and neurological and psychiatric disorders [ 19 ].…”