Residency Doctor Zhejiang Cancer Hospital Hangzhou, Zhejiang, China (People's Republic)
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Purpose: Radiation resistance is a crucial determinant for the treatment failure and disease progression of lung cancer. Dissecting the molecular mechanisms of radiation resistance is helpful for developing novel and effective strategies of radiation sensitization. LSD1 (Lysine-specific demethylase is the first identified histone demethylase, it is actively involved in vast range of biological processes through regulating the methylation status of histones and non-histone proteins. Recently, it was reported that LSD1 is involved in DNA damage response, however, whether LSD1 is involved in the development of radiation resistance, and how does LSD1 be regulated in the upstream, especially the post-translational modification, remain elusive.
Methodology: Western Blotting (WB) and qRT-PCR (Quantitative Real-time PCR) were used to detect the expression of LSD1 on protein and mRNA expression levels, respectively. Co-immunoprecipitation (Co-IP) and in vitro protein pull-down assay was used for protein-protein interaction studies. Protein half-life and in vivo ubiquitylation assays were used for detecting the protein stability of LSD1. For the biological related experiments, ATPlite, colony formation assay, micro-irradiation laser assay, NHEJ linearized plasmid assay and clonogenic survival assay were used to detect the biological functions of LSD1.
Results: Here we report that LSD1 plays pivotal roles in the radiation resistance development of lung cancer. Mechanically, DNA damage stress triggers ATM-mediated neddylation modification of LSD1, which antagonizes its ubiquitylation and degradation. The upregulated LSD1 further facilitates non-homologous end-joining (NHEJ) repair to confer radiation resistance of lung cancer cells.
Conclusions: Our study reveals a novel regulation of LSD1 by neddylation pathway and determines its involvement in radiation resistance development, providing new insights into mechanism and rational approaches to radiation of lung cancer by targeting LSD1.
