The oncogenic role of BMAL2 in non-small cell lung cancer: MRPL15-mediated regulation of apoptosis and ferroptosis.

Previous studies have demonstrated that the overexpression of circadian rhythm-related gene basic helix-loop-helix ARNT like 2 (BMAL2) promotes the progression of malignant tumors. However, its downstream targets remain largely unclear. The aim of the present study was to explore the significance of BMAL2/mitochondrial ribosomal protein L15 (MRPL15) in non-small cell lung cancer (NSCLC). We found that BMAL2 was upregulated in NSCLC tissues, as compared with normal tissues. NSCLC patients with late stage exhibited a high expression of BMAL2. In vitro, BMAL2 overexpression promoted the growth of NSCLC cells. Mechanistically, BMAL2 potentiated the expression of MRPL15 at the mRNA and protein levels. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR results showed that BMAL2 enhanced the transcription activity of the MRPL15 gene by binding to its promoter. MRPL15 upregulation accelerated the cell cycle progression of NSCLC cells. Ferroptosis and apoptosis were clearly inhibited by MRPL15. BMAL2 overexpression promoted the tumorigenesis ability of NSCLC cells, which was suppressed by MRPL15 knockdown. The induction of ferroptosis and apoptosis completely reversed the oncogenic function of BMAL2 following MRPL15 knockdown. In addition, there was a positive correlation between BMAL2 and MRPL15 in patients with NSCLC. BMAL2 or MRPL15 overexpression was associated with poor prognosis NSCLC. In conclusion, the present findings demonstrated that BMAL2 exhibited a tumor promoting effect in NSCLC through the regulation of MRPL15-mediated cell cycle procession, apoptosis and ferroptosis. The induction of apoptosis and ferroptosis are a promising strategy for the treatment of NSCLC patients with a high BMAL2 expression.