Abstract
Lung cancer is a multi-etiological disease and radon is known as the second most common risk factor for the disease. The tumor suppressor gene TP53 is commonly mutated in human lung cancer, thus contributing to the alteration of mitochondrial outer membrane permeability (MOMP). Thus, this study aimed to investigate the role of the P53-mediated mitochondrial pathway in radon-induced lung cancer. Long-term radon exposure downregulated P53, enhanced mitochondrial membrane potential (MMP), and increased mitochondrial DNA copy number in BEAS-2B cells, as well as in the lung tissues of mice exposed to radon. The above effects significantly contributed to the radon-induced malignant transformation of BEAS-2B cells. In addition, high-throughput sequencing analysis revealed that BTG2 downregulation was involved in the P53 mitochondrial pathway-mediated radon-induced malignant transformation. BTG2 overexpression significantly restored the TP53-mediated alterations in MOMP, apoptosis, and MMP. Mechanically, TP53 downregulation was regulated by m6A demethylase ALKBH5, which was validated by treatment of ALKBH5 inhibitor IOX1 and mRNA stability assay in BEAS-2B and H1299 cells. Our research shows that the ALKBH5-mediated downregulation of TP53 affects the carcinogenesis of radon, and the BTG2 suppression in the P53-mediated mitochondrial pathway plays an important role in radon-induced lung cancer.