KDM5D histone demethylase mediates p38α inactivation via its enzymatic activity to inhibit cancer progression.

The p38 MAP kinase (MAPK) signaling pathway plays pivotal roles in various cellular processes. Phosphorylation serves as a canonical way to regulate p38α activation through a phosphorylation cascade. Thus, understanding the mechanism governing p38α phosphorylation is important. The present study demonstrated that p38α undergoes methylation at K165, which promote its phosphorylation in tumor cells. Inhibition of p38α methylation impairs p38α phosphorylation, repressing tumor progression in vitro and in vivo. Mechanistically, KDM5D is a demethylase that interacts with p38α, mediating demethylation at K165 and inhibiting p38α phosphorylation. Moreover, KDM5D is expressed at low levels in non-small cell lung cancer (NSCLC), and high KDM5D expression is positively correlated with cancer survival. KDM5D markedly inhibits cell proliferation and migration via inactivating p38α, thereby slowing cancer progression in xenograft models. In summary, these findings highlight KDM5D as a demethylase of p38α at K165, elucidating a unique role for lysine demethylation in integrating cytoplasmic kinase-signaling cascades. The present results revealed the critical role of KDM5D in suppressing tumor progression, suggesting that KDM5D can serve as a potential drug target for combating hyperactive p38α-driven lung cancer.