Adenosine-to-inosine (A-to-I) RNA editing is a prevalent post-transcriptional modification that affects the structure and function of RNA molecules, including double-stranded RNA, tRNA, microRNA, and viral RNA. This modification is primarily catalyzed by adenosine deaminases acting on RNA (ADARs) and tRNA-specific adenosine deaminases (ADATs). Aberrant A-to-I editing is linked to cancer development and progression, influencing the expression of oncogenes and tumor suppressor genes. Recent advancements in next-generation sequencing and bioinformatics have enabled a global understanding of A-to-I editing, revealing its critical role in various pathological processes. The review also discusses the potential of leveraging endogenous ADARs for programmable RNA editing in cancer therapy.
Key Insights from the review include:

1. A-to-I Editing in Cancer: A-to-I RNA editing is significantly involved in cancer development and progression. Aberrant levels of A-to-I editing are associated with the regulation of oncogenes and tumor suppressor genes, contributing to tumorigenesis.
2. Enzymes Involved: The primary enzymes responsible for A-to-I editing are ADARs and ADATs. ADARs are broadly expressed and play a crucial role in various tissues, while ADATs specifically target tRNAs. The testis-specific ADAD protein family is also essential for male fertility.
3. Therapeutic Potential: Novel approaches, such as LEAPER and CLUSTER, aim to leverage endogenous ADARs for targeted RNA editing. These methods show promise in precise manipulation of A-to-I editing, potentially offering new avenues for cancer treatment.
4. Context-Dependent Roles: The functions of ADAR1 and ADAR2 in cancer are context-dependent and vary across different cancer types. ADAR1 is often overexpressed and promotes tumorigenesis, while ADAR2 is more frequently associated with tumor suppression.

The review highlights the complex and multifaceted role of A-to-I RNA editing in cancer. While A-to-I editing is a double-edged sword, with ADAR1 often promoting tumorigenesis and ADAR2 having tumor-suppressive properties, the context-specific nature of these enzymes underscores the need for further research. Developing inhibitors targeting A-to-I pathways and leveraging endogenous ADARs for programmable editing offer promising therapeutic strategies for cancer treatment. The work entitled “ Adenosine-to-inosine RNA editing in cancer: molecular mechanisms and downstream targets” was published on Protein & Cell (published on Aug. 10, 2024).
DOI: 10.1093/procel/pwae039