Ancient Adversary - HERV-K (HML-2) in Cancer

Abstract

Human endogenous retroviruses (HERV), ancient integrations of exogenous viruses, make up 8% of our genome. Long thought of as mere vestigial genetic elements, evidence is now accumulating to suggest a potential functional role in numerous pathologies including neurodegenerative diseases, autoimmune disorders, and multiple cancers. The youngest member of this group of transposable elements is HERV-K (HML-2). Like the majority of HERV sequences, significant post-insertional mutations have disarmed HERV-K (HML-2), preventing it from producing infectious viral particles. However, some insertions have retained limited coding capacity, and complete open reading frames for all its constituent proteins can be found throughout the genome. For this reason HERV-K (HML-2) has garnered more attention than its peers. The tight epigenetic control thought to suppress expression in healthy tissue is lost during carcinogenesis. Upregulation of HERV-K (HML-2) derived mRNA and protein has been reported in a variety of solid and liquid tumour types, and while causality has yet to be established, progressively more data are emerging to suggest this phenomenon may contribute to tumour growth and metastatic capacity. Herein we discuss its potential utility as a diagnostic tool and therapeutic target in light of the current in vitro, in vivo and clinical evidence linking HERV-K (HML-2) to tumour progression.

Keywords: HERV human endogenous retroviruses; biomarker; cancer; epigenetics; metastasis; transposable element (TE).

Figure 1

HML-2 Proviral Structure. HML-2 proviral integrations have either a type I or type II genome delineated by the respective presence (type I) or absence (type II) of a 292 bp deletion at the pol/env boundary. The full length transcript codes for the Gag precursor and Gag-Pro/Gag-Pro-Pol fusion proteins that are processed by the viral protease and cellular proteasome respectively. Singly sliced HML-2 mRNA encodes the Env protein, while a secondary slicing event of env mRNA gives rise to the Rec (type II) or Np9 (type I) accessory proteins. Splice donor (SD) and splice acceptor (SA) sites are indicated (type II loci combine SD2 and SA2 for rec splicing while type I loci contain the alternative SD3 site for np9 transcript generation). Created with BioRender.com.

Figure 2

Potential Mechanisms and Molecular Underpinnings of HML-2 Induced Oncogenesis/Tumour Promotion. HML-2 Gag and Env are known to be immunogenic and may contribute to chronic tumour-promoting inflammation. In addition, HML-2 ssRNA binds and activates Toll-like receptor 8 (TLR8), while HML-2 and other HERV-derived dsRNAs may activate Toll-like receptor 3 (TLR3) and the melanoma differentiation-associated protein 5 (MDA5)/mitochondrial antiviral signalling protein (MAVS) pathway to elicit a type I IFN response and nuclear factor -κB (NF-κB) activation. Conversely, Env has been shown to possess an immunosuppressive domain and may inhibit peripheral blood mononuclear cell (PBMC) activation via interleukin-10 (IL-10) to aid tumour immune escape. Rec inhibits the androgen receptor (AR) repressor proteins human small glutamine-rich tetratricopeptide repeat (hSGT) and testicular zinc finger protein (TZFP), potentially forming a positive feedforward loop driving chronic HML-2 transcription and AR activation. Np9 has been shown to activate multiple oncogenic signalling pathways (including ERK, Akt, NOTCH and β-catenin), while both accessory proteins have been shown to induce c-Myc transcriptional derepression by inhibiting the promyelocytic leukaemia zinc finger protein (PLZF). Np9 can also bind and inhibit the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2), however, the impact of the resultant p53 stabilisation would likely depend on p53 mutational status. Finally, HML-2 insertions may regulate neighbouring gene expression by (1) recruiting histone methyltransferases (HMT) or histone acetyltransferases (HAT) to regulate chromatin accessibility, or (2) serve as alternative enhancer regions that drive adjacent gene transcription. Created with BioRender.com.