p53 transcriptionally activates DCP1B to suppress tumor progression and enhance tumor sensitivity to PI3K blockade in non-small cell lung cancer

Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients, is characterized by its aggressive nature and poor prognosis. In this study, we identify decapping mRNA 1B (DCP1B) as a tumor suppressor gene that is transcriptionally regulated by p53. DCP1B is found to inhibit the growth and migration of NSCLC cells. Consistently, the level of DCP1B expression is decreased in NSCLC tissues, and its low expression is associated with NSCLC patients’ unfavorable outcomes. Mechanistic investigations reveal that DCP1B promotes the turnover of mitogen-activated protein kinase 4 (MAPK4) mRNA, and the activation of p53 reduces the expression level of MAPK4 partially through DCP1B. Notably, overexpression of MAPK4 can drive AKT phosphorylation independent of phosphoinositide 3-kinase (PI3K), thus neutralizing the anti-tumor activity of the PI3K inhibitor in NSCLC cells. Moreover, the p53 agonist combined with the PI3K inhibitor can suppress NSCLC proliferation synergistically in vitro and in vivo. Collectively, this study not only uncovers the function and mechanism of the p53-DCP1B-MAPK4 axis in suppressing NSCLC progression but also suggests a promising combination strategy for treating NSCLC.