The clathrin adaptor AP1-S1 is associated with immune infiltration and HLA loss, as a potential therapeutic target in lung adenocarcinoma

Abstract

The clathrin adaptor protein 1 (AP1) plays a pivotal role in the endocytosis of cell surface proteins and transportation between the golgi apparatus and lysosomes. Despite its critical functions, the implications of AP1 dysregulation in human cancers have yet to be elucidated. The structural analysis of AP1 subunits was conducted utilizing data from the Protein Data Bank (PDB), which is composed of four subunits: AP1-S1, AP1-B1, AP1-G1, and AP1-M1. Notably, the expression levels of AP1 subunits exhibit significant variability between tumor and normal tissues across different cancer types using data from the CPTAC, GEO, and TCGA databases. Kaplan-Meier (K-M) curve analysis has revealed that certain AP1 subunits are correlated with patient prognosis in various cancers. For instance, the AP1-S1 subunit is related to poor survival outcomes in head and neck squamous carcinoma, clear cell renal cell carcinoma, and lung adenocarcinoma. Furthermore, the aberrant expression of AP1-S1 demonstrated a negative correlation with immune cells infiltration, particularly in lung adenocarcinoma. Concurrently, a significant negative relationship between AP1-S1 and HLA molecules was observed, indicating a potential mechanism for AP1-induced HLA degradation. In vitro experiments demonstrated that the knockdown of AP1-S1 led to an upregulation of HLA-B protein expression and inhibited the viability, migration, and invasion capabilities of tumor cells in lung adenocarcinoma cell lines, specifically A549 and H1299. Immunohistochemical staining further revealed the abnormal expression of AP1-S1 in lung adenocarcinoma specimens. Through a comprehensive pan-cancer multi-omics analysis and experimental validation, this study explored the prognostic significance of four AP1 subunits. Additionally, it examined the regulatory relationship between AP1-S1 and HLA-B, which may play a role in immune escape. Additionally, the research identified AP1-S1 as a valuable biomarker and a potential target for treatment of lung adenocarcinoma.