Monoubiquitination of histone H2B (H2Bub1) is an important chromatin modification that plays multiple roles in transcription, mRNA processing, DNA repair, cell differentiation, and maintenance of stemness. Recent studies have indicated that dysregulation of H2Bub1 and the resulting alterations of global gene expression are key contributors in cellular transformation and metastasis. However, the importance of H2B ubiquitination in lung cancer is unknown. Here, by using immunohistochemical analysis (IHC), we have demonstrated that the protein level of H2Bub1 is frequently decreased in a cohort of human lung cancer tissues in comparison to paired adjacent normal tissues. We also found that decrease in H2Bub1 is associated with increased cellular proliferation, as measured by Ki67, and is associated with decreased overall survival. Furthermore, using RNA-seq and transcriptional profiling analysis, we identified that reduction of H2Bub1 via attenuating the expression of histone H2B E3 ubiquitin ligase ring finger protein 20 (RNF20) leads to significant changes of global gene expression, modulating multiple malignancy-promoting genes, including c-Met, E2F2, and BMF. Signaling pathways including p53, DNA replication, DNA repair, and cellular proliferation, and regulation of apoptosis in lung cancer cells are also altered. Additionally, we have further shown that decrease of H2Bub1 by RNF20 knockdown significantly promotes growth, migration/invasion, and strongly enhances resistance to cytotoxic chemotherapy-induced apoptosis in lung cancer cells. Our findings suggest that dysregulation of H2Bub1 signaling may play an important role in growth and drug resistance of lung cancers, and may potentially serve as a prognostic biomarker and therapeutic target for lung cancer patients.

Citation Format: Keqiang Zhang, Jinhui Wang, Xiwei Wu, Theresa A. Reno, Tommy R. Tong, Jae Kim, Dan Raz. Decreased H2B monoubiquitination is associated with enhanced proliferation and resistance to apoptosis in human lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4523.