DACH1 inhibits lung adenocarcinoma invasion and tumor growth by repressing CXCL5 signaling

Abstract

Whole-genome and transcriptome sequencing of non-small cell lung cancer (NSCLC) identified that DACH1, is a human homolog of drosophila gene dac, is involved in NSCLC. Here we showed that expression of DACH1 was significantly decreased in human NSCLC tissues and DACH1 abundance was inversely correlated with tumor stages and grades. Restoration of DACH1 expression in NSCLC cells significantly reduced cellular proliferation, clone formation, migration and invasion in vitro, as well as tumor growth in vivo. Unbiased screen and functional study suggested that DACH1 mediated effects were dependent in part on suppression of CXCL5. There was an inverse correlation between DACH1 mRNA levels and CXCL5 in both lung cancer cell lines and human NSCLC tissues. Kaplan-Mier analysis of human NSCLC samples demonstrated that high DACH1 mRNA levels predicted favorable prognosis for relapse-free and overall survival. In agreement, high CXCL5 expression predicted a worse prognosis for survival.

CXCL1 as an Unfavorable Prognosis Factor Negatively Regulated by DACH1 in Non-small Cell Lung Cancer

“…Our previous study has demonstrated that DACH1 was a tumor suppressor factor and negatively correlated with CXCL5 (22). And CXCL5 contributed to the tumorigenesis and poor prognosis in NSCLC (62).…”

The DACH/EYA/SIX gene network and its role in tumor initiation and progression

“…Apparently, lung cancer patients with a low expression of DACH1 as well as a high level of CXCL5 suffered an unfavorable prognosis. 89 RDGN functions in opposition to EYA/SIX. EYA1 is enriched with cyclin D1 in luminal B breast cancer expression in 2,154 breast cancer samples and predicts a poor prognosis.…”

“…The evidence from our study indicated that CXCL5 was a downstream target of the DACH1‐mediated repression of cell invasion and tumorigenesis. Apparently, lung cancer patients with a low expression of DACH1 as well as a high level of CXCL5 suffered an unfavorable prognosis …”

The retinal determination gene network: from developmental regulator to cancer therapeutic target

“…Dach1 gene deletion in mice was shown to dramatically increase IL-8 and IL-6 abundance by nearly 1000-fold and thus promote prostate cancer cellular migration [60]. CXCL5 is another downstream target whereby DACH1 inhibits lung tumorigenesis and metastasis [61]: endogenous DACH1 negatively regulates CXCL signaling to inhibit cytokine secretion and restrain malignant cell growth and migration. DACH1 also was found to repress bFGF-induced tumor initiation in glioma cells [62].…”