PP4R1 accelerates the malignant progression of NSCLC via up-regulating HSPA6 expression and HSPA6-mediated ER stress.

Protein phosphatase 4 (PP4) plays an indispensable regulatory part in the development and malignant progression of multifarious tumors. Nevertheless, the function of protein phosphatase 4 regulatory subunit 1 (PP4R1), a vital regulatory subunit of PP4, in tumors especially in lung cancer remains blurred. Therefore, this study aimed to investigate the function and mechanism of PP4R1 in the development of non-small cell lung cancer (NSCLC). We analyzed the clinical correlation of PP4R1 based on the TCGA database by UALCAN (https://ualcan.path.uab.edu/index.html) and found that hyper-expression of PP4R1 mRNA was related to the severe prognosis in NSCLC. The subsequent cellular experiments confirmed that the proliferation, colony growth, migration as well as invasion of H1299 and HCC827 were significantly enhanced after PP4R1 overexpression treatment in vitro. Results from animal experiments pointed out that tumors exhibited stronger growth and lung metastatic capacities due to the overexpression of PP4R1. The bioinformatics analysis, including RNA-seq, showed us that PP4R1 significantly promoted the expression of several HSP70 family member genes, with a particularly marked increase in HSPA6, and the enrichment analyses illustrated that the differentially expressed genes (DEGs) were enriched in those pathways related to protein folding. More importantly, the overexpression of HSPA6 resulted in the same malignant progression of NSCLC as PP4R1 overexpression, and both concomitant with the activation of endoplasmic reticulum (ER) stress. In aggregate, PP4R1 contributed to the malignant progression of NSCLC via up-regulating HSPA6 expression and then activating ER stress.