BHLHE41 promotes U87 and U251 cell proliferation via ERK/cyclinD1 signaling pathway

PURPOSE: The biological functions of BHLHE41 in the proliferation of glioblastoma remained unexplored. We aimed to investigate the biological roles and underlying molecular mechanisms of BHLHE41 in glioblastoma. MATERIALS AND METHODS: We used multiple methods, including Western blot analysis, soft agar colony-formation assay, CCK8 assay, and flow cytometry, to evaluate the changes in multiple cellular functions after BHLHE41 knockdown or overexpression in U87 and U251 cell lines. The TCGA database was then used to analyze the associations between BHLHE41 expression with clinicopathological factors and the overall survival (OS) of glioma patients. RESULTS: This study determined that overexpression of BHLHE41 promoted glioma cell proliferation and colony formation. Besides, BHLHE41 upregulated cyclinD1, cyclinD3, and cyclinE1 expression and drove phase transition from G1 to S and G2 phases by upregulating these cyclins. In contrast, knockdown of BHLHE41 had an opposite effect on all of these parameters. However, BHLHE41 had no effect on apoptosis. Moreover, BHLHE41 activated MAPK/ERK signaling pathway to upregulate cyclinD1 expression. After the ERK signal pathway was blocked by a specific inhibitor, SCH772984, cyclinD1 upregulation was reversed. Furthermore, the median OS of low-grade glioma (LGG) patients with low to median level of BHLHE41 was 22.6 months, longer than that of the patients with high level of BHLHE41 (21.0 months). CONCLUSION: BHLHE41 has an important role in the proliferation of glioblastoma and could serve as a novel candidate for targeted therapy of glioblastoma.