ADAR1 enhances tumor proliferation and radioresistance in non-small cell lung cancer by interacting with Rad18.

Abstract

Purpose: Posttranslational modification significantly contributes to the transcriptional diversity of tumors. Adenosine deaminase acting on RNA 1 (ADAR1) and its mediated adenosine-to-inosine (A-to-I) editing have been reported to influence tumorigenesis across various cancer types. Nevertheless, the relationship between ADAR1 and radioresistence remains to be elucidated.

Methods: The protein expression was detected by immunohistochemistry and Western Blot, while the mRNA expression was measured by RT-qPCR. The tumor growth was evaluated by CCK8, colony formation assays, EdU assay, and in-vivo mouse model. γ-H2AX foci formation, neutral comet tailing assay, and clonogenic cell survival assay were performed to determine the DNA damage and radiosensitivity. RNA-seq was conducted to identify the main downstream effector. The interaction between ADAR1 and Rad18 was examined by immunofluorescence and co-immunoprecipitation.

Results: We reported that ADAR1 was upregulated and correlated with poor prognosis in non-small cell lung cancer (NSCLC). In addition, we demonstrated that silencing ADAR1 significantly impaired tumor growth and improved tumor sensitivity to radiotherapy in vitro and in vivo. Mechanistically, we found that Rad18, which has been established as a versatile modulator of DNA repair, was the major downstream effector of ADAR1. ADAR1 not only regulated Rad18 mRNA expression by E2F3 but also colocalized and interacted with Rad18. Finally, our rescue experiments demonstrated that ADAR1's protumorigenic functions were partially dependent on Rad18.

Conclusion: Our results revealed the role of ADAR1 in cooperation with Rad18 in modulating oncogenesis and radioresistance in NSCLC for the first time, and suggested the therapeutic potential of targeting ADAR1 in overcoming radioresistance.