Histone H1.4K75 acetylation promotes tumor growth and migration by regulating p53 and ERK1/2 pathway in non-small lung cancer.

Histone H1.4 is a member of the linker histone H1 family, and its post-translational modifications (PTMs) are essential for its function. However, the role of H1.4 PTM in cancer development is not fully understood. Here, we report the discovery of a previously uncharacterized acetylation site at lysine 75 (K75) of H1.4 in non-small cell lung cancer (NSCLC). Point mutation of K75 with arginine (H1.4K75R) markedly suppressed cellular viability and migration in A549 and H1299 cells, and inhibit tumor growth in xenografts mouse models. Moreover, RNA-sequencing and Western Blot analyses revealed that H1.4K75 acetylation orchestrates dual regulatory effects, potentiating ERK1/2 signaling while repressing the p53 pathway. In summary, our studies show that H1.4K75 acetylation is essential for cell viability, migration and tumor growth in NSCLC, and may be a therapeutic target for NSCLC.