ADAR1 promotes cancer fitness by buffering endogenous RNA sensing.

Abstract

Tumors exploit multifaceted strategies to survive and avoid destruction by the immune system. The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) regulates double-stranded (ds)RNA metabolism by catalyzing the adenosine-to-inosine (A-to-I) change, which is one of the most prevalent RNA modifications in mammalian cells. dsRNA binding and editing by ADAR1 skew the activation of cytosolic RNA sensors of innate immunity generally occurring during viral infections or upon accumulation of unedited endogenous RNAs. ADAR1 expression and global A-to-I RNA editing levels are elevated across a broad range of tumor types, where they promote cancer cell survival by suppressing endogenous RNA sensing pathways, thereby preventing the activation of protective inflammatory and cell death programs. Moreover, ADAR1 deregulation in stromal and immune cells leads to the reprogramming of tumor microenvironment towards a cancer-permissive condition. Here we describe different functions of ADAR1 that nurture cancer features. We propose that through both editing-dependent and -independent mechanisms ADAR1 plays a general, not ancillary, role in increasing tumor cell fitness and therefore its modulation may be addressed for developing novel approaches in anticancer strategies.