Reactivation of Endogenous Retroelements in Cancer Development and Therapy

Charles A. Ishak,Daniel D. De Carvalho

doi:10.1146/annurev-cancerbio-030419-033525

Abstract

Domesticated retroelements contribute extensively as regulatory elements within host gene networks. Upon germline integration, retroelement mobilization is restricted through epigenetic silencing, mutational degradation, and innate immune defenses described as the viral mimicry response. Recent discoveries reveal how early events in tumorigenesis reactivate retroelements to facilitate onco-exaptation, replication stress, retrotransposition, mitotic errors, and sterile inflammation, which collectively disrupt genome integrity. The characterization of altered epigenetic homeostasis at retroelements in cancer cells also reveals new epigenetic targets whose inactivation can bolster responses to cancer therapies. Recent discoveries reviewed here frame reactivated retroelements as both drivers of tumorigenesis and therapy responses, where their reactivation by emerging epigenetic therapies can potentiate immune checkpoint blockade, cancer vaccines, and other standard therapies.

Highlights

Current models of the molecular genetics that underlie cancer development and therapeutic response are predominantly based upon characterizations of the 1–2% of protein-coding DNA sequences in the human genome and the interactions of their protein products
Concepts of mobile endogenous retroviruses (ERVs) that could be inherited through the germline emerged
Dividing cancer cells take up these agents more rapidly than postmitotic somatic cells, resulting in genomewide DNA hypomethylation, resurrection of retrotransposons, and double-stranded RNAs (dsRNAs)-induced viral mimicry responses that promote antitumor cytolytic T cell activity (Chiappinelli et al 2015, Roulois et al 2015)

Summary

Introduction

Current models of the molecular genetics that underlie cancer development and therapeutic response are predominantly based upon characterizations of the 1–2% of protein-coding DNA sequences in the human genome and the interactions of their protein products. Recent studies described below reveal that repetitive elements contribute extensively as regulatory elements to enable activation of viral mimicry responses against repeat RNA in cancer cells. These observations illustrate how exapted LTRs regulate viral mimicry responses and establish the integrity of immune cell identity.

Results

Conclusion