H1.4 is one of the 11 variants of linker histone H1, and is associated with tumorigenesis and development of various cancers. However, it is unclear for the role of histone H1.4 in non-small cell lung cancer (NSCLC). In this study, we found that overexpression of H1.4 significantly inhibited the cell viability, migration, invasion and epithelial-mesenchymal transition (EMT) processes, whereas silencing H1.4 by shRNA knockdown promoted these processes in NSCLC cell lines A549 and H1299. We further showed that H1.4 overexpression reduced ERK1/2 expression or its phosphorylation levels, while H1.4 knockdown increased ERK1/2 expression or phosphorylation levels in NSCLC. Furthermore, we demonstrated that H1.4 bound to the promoter of ERK1/2, and acted as a transcriptional suppressor to inhibit ERK1/2 expression in A549 or H1299 cells. Importantly, we found that ERK ecto-expression can largely recovered the inhibitory effects of H1.4 on cell viability, migration, invasion and EMT processes. In summary, our study reveals that the H1.4-ERK pathway is crucial for cell viability, migration, invasion and EMT of NSCLC and could be a therapeutic target for NSCLC.

H1.4是接头组蛋白H1的11种变体之一，与多种癌症的发生和发展相关。然而，组蛋白 H1.4 在非小细胞肺癌 (NSCLC) 中的作用尚不清楚。在这项研究中，我们发现 H1.4 的过表达显着抑制了 NSCLC 细胞系 A549 和 H1299 中的细胞活力、迁移、侵袭和上皮间质转化 (EMT) 过程，而通过 shRNA 敲低沉默 H1.4 则促进了这些过程。我们进一步表明，H1.4 过表达降低了 NSCLC 中的 ERK1/2 表达或其磷酸化水平，而 H1.4 敲低则增加了 ERK1/2 表达或磷酸化水平。此外，我们证明H1.4与ERK1/2的启动子结合，并作为转录抑制因子抑制A549或H1299细胞中ERK1/2的表达。重要的是，我们发现ERK外表达可以在很大程度上恢复H1.4对细胞活力、迁移、侵袭和EMT过程的抑制作用。总之，我们的研究表明，H1.4-ERK 通路对于 NSCLC 的细胞活力、迁移、侵袭和 EMT 至关重要，可能成为 NSCLC 的治疗靶点。