Abstract
KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane- and KRASG12D-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRAS-mutant NSCLC and propose the clinical benefit of PIERCE1.
Highlights
These authors contributed : Jae-il Roh, Jaehoon Lee
The results showed that patients with low PIERCE1 expression had significantly improved overall and progression-free survival rates compared to patients with high expression levels (Fig. 1a and Supplementary Fig. 1a), suggesting that PIERCE1 might be involved in lung tumorigenesis
Since tribbles homolog 3 (TRIB3) expression is mainly controlled by ATF4CHOP transcription factors that are activated upon ER stress conditions [36], we examined whether the changes in expression levels by PIERCE1 KD were enriched in C/ EBP homologous protein (CHOP) target gene sets using gene set enrichment analysis (GSEA) [37]
Summary
Once KRAS is mutated, it constitutively activates its downstream targets, such as MAPK and AKT pathways, resulting in increased cell proliferation and survival [10]. Enhanced tumorigenesis has been observed following genetic inhibition of TRIB3, along with a rise in AKT phosphorylation (pAKT), in the presence of activating mutations in HRAS and deletion of PTEN [18]. Under specific conditions such as arsenite treatment and endoplasmic-reticulum (ER) stress, transcriptional activation of TRIB3 can be performed through transcription factors, such as activating transcription factor 4 (ATF4)-C/ EBP homologous protein (CHOP) [20, 21]. This study provides insights into a novel and promising therapeutic strategy that inhibits PIERCE1 in KRAS-mutant type NSCLC
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