CYP3A5 suppresses metastasis of lung adenocarcinoma through ATOH8/Smad1 axis

摘要

Cytochrome P450 3A5 (CYP3A5) maintains primary roles in toxic metabolism, catalyzes redox reaction, and contributes to chemotherapeutic resistance. However, the mechanism of CYP3A5 in carcinogenesis remains largely undefined. Here, we investigated a novel role of CYP3A5 inhibiting the metastasis in lung adenocarcinoma (LUAD) via ATOH8/Smad1 axis. We found that CYP3A5 was generally down-regulated in LUAD by RT-PCR, western blot and immunohistochmeistry (IHC) in tissues and cell lines. Low expression of CYP3A5 was significantly associated with poor prognosis of LUAD patients. Functionally, ectopic expression of CYP3A5 could substantially inhibit the migration and invasion in vitro. Consistently, up-regulation of CYP3A5 dramatically suppressed metastatic ability in vivo. Mechanistically, high-throughput phosphorylation chip indicated that CYP3A5 significantly decreased the phosphorylation of Smad1, resulting in suppression of metastasis. Furthermore, bioinformatics analysis and co-immunoprecipitation (Co-IP) experiments uncovered that CYP3A5 interacted with ATOH8, and the interaction, in turn, mediated in-activation in the Smad1 pathway. The combined IHC panel, including CYP3A5 and phosphorylation of Smad1, exhibited a better prognostic value for LUAD patients than any of these components individually. Taken together, CYP3A5 repressed activation of Smad1 to inhibit LUAD metastasis via interacting with ATOH8, indicating a novel potential mechanism of CYP3A5 in LUAD progression.