Characterizing and Targeting Genes Regulated by Transcription Factor MYBL2 in Lung Adenocarcinoma Cells

Abstract

Overexpression of MYBL2 is associated with poor survival of lung adenocarcinoma patients, but the molecular mechanism by which it regulates transcription and carcinogenesis has not yet been elucidated. In this study, we performed ChIP-seq using an MYBL2-targeted antibody and discovered that MYBL2 primarily binds to the promoters of highly expressed genes in lung adenocarcinoma cells. Using a knockdown experiment of MYBL2 and global transcriptome profiling, we identified that over a thousand genes are dysregulated by MYBL2, and MYBL2 acts as a transcriptional activator in lung adenocarcinoma cells. Moreover, we revealed that the binding sites of FOXM1 are largely shared with MYBL2 binding sites, and genes involved in cell cycle phase transitions are regulated by these transcription factors. We furthermore investigated the effect of a previously reported FOXM1 inhibitor, FDI-6, in lung adenocarcinoma cells. We demonstrated that FDI-6 decreases the proliferation of lung adenocarcinoma cells and inhibits the activities of FOXM1 as well as MYBL2. Moreover, we found that genes involved in cell death and cell cycle are inhibited by FDI-6. Overall, our findings suggest that MYBL2 and FOXM1 activate cell cycle genes together, acting as oncogenic transcription factors in lung adenocarcinoma cells, and they are potential treatment targets for the disease.