Effect of defective H2B ubiquitination on the malignancy and repair of DNA double breaks and its significance in lung adenocarcinoma

Lung cancer is the leading cause of cancer-related mortality, with a notably low five-year survival rate due to the limited availability of effective treatments. Monoubiquitination of histone H2B at lysine 120(uH2B) exerts a tumor-suppressive effect in cancer through multiple mechanisms, including the regulation of transcriptional activity and DNA damage response. Ring Finger Protein 20 (RNF20), a key E3 ubiquitin ligase, plays a central role in this process. However, the role of RNF20 in lung adenocarcinoma (LUAD) progression is unknown. In this study, the functional characterization of the role and molecular mechanism of LUAD were examined using a series of biological and cellular approaches in vitro and in vivo. Our work shows the expression of uH2B is significantly reduced in LUAD patients and is correlated with prognosis. Similarly, RNF20 expression is also markedly decreased in LUAD. Knockdown of RNF20 promoted the proliferation and migration of A549 cells while simultaneously decreasing uH2B expression. Additionally, RNF20 knockdown impaired the DNA damage repair capacity of LUAD cells. RNF20-silenced A549 cells exhibited heightened sensitivity to both the Cisplatin and PARP inhibitor Olaparib. These findings provide an important foundation for further understanding the molecular mechanisms of lung adenocarcinoma and developing new treatment strategies.