HERC4 downregulates KRT19 to promote lung adenocarcinoma, migration, invasion and EMT.

ABSTRACT:

Background

Metastasis is a major cause of treatment failure and poor prognosis in lung adenocarcinoma (LUAD). Epithelial-mesenchymal transition (EMT) plays a crucial role in promoting LUAD metastasis. Pulmonary sarcomatoid carcinoma (PSC), a highly aggressive non-small cell lung cancer subtype, contains both carcinomatous component (CaC) and sarcomatous component (SaC) with strong metastatic potential. Previous studies have shown that EMT contributes to the formation of Sac in PSC.

Methods

The differential expression of KRT19 between SaC and CaC in PSC was screened and validated using immunohistochemistry. GO, KEGG analysis were conducted to investigate the potential mechanism of KRT19. The CCK-8, wound healing, transwell assay and mouse model were used to confirm the impact of KRT19 on cell proliferation, migration and invasion in LUAD. The upstream regulatory molecules of KRT19 were identified and validated through CO-IP, GST Pull-down Assay and ubiquitination experiments.

Results

KRT19 was found to be downregulated in SaC compared to CaC and LUAD. Knock down of KRT19 in A549 and PC-9 cells led to EMT, decreased adhesion, and increased proliferation and metastasis. HERC4 was identified as a potential upstream regulator of KRT19, with its expression negatively correlated with KRT19 levels. HERC4 promoted KRT19 ubiquitination, leading to its downregulation.

Conclusion

KRT19 downregulation promoted LUAD cell EMT, enhancing metastatic potential. HERC4 functioned as an upstream regulator that suppresses KRT19 expression by promoting its ubiquitination.

SUBMITTER: Sun HJ 

PROVIDER: S-EPMC12630102 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature