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

SIMPLE SUMMARY: The clinical behavior and progression of lung cancer vary case by case. Therefore, understanding the factors that contribute to aggressive lung cancer cases is crucially needed. Previously, we showed that transcription factor MYBL2 expression is associated with the survival of lung adenocarcinoma patients. In this study, we characterized the functions of MYBL2 in lung adenocarcinoma cells by generating global binding profiles of MYBL2 and transcriptome profiles upon knockdown experiments. We discovered that MYBL2 regulates cell cycle genes by binding to the promoters of highly expressed genes in lung adenocarcinoma cells working with FOXM1. Moreover, we found that a previously reported FOXM1 inhibitor, FDI-6 (forkhead domain inhibitor 6), suppresses lung adenocarcinoma cell proliferation by inhibiting the activities of MYBL2 and FOXM1 and controlling cell death and cell cycle genes. Our findings provide valuable insights into the molecular mechanisms of aggressive lung cancer and suggest potential targets and treatments for the disease. 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.