DDX6-mediated CACHD1 mRNA stabilization enhances non-small cell lung cancer progression via activation of FAK signaling

DDX6, a member of the conserved DEAD-box ATPase/helicase family, is involved in the regulation of target mRNA abundance. Our previous study shows that DDX6 can promote non-small cell lung Cancer (NSCLC) progression. However, the underlying mechanism is still unclear. In the present study, we performed RNA immunoprecipitation (RIP) and RNA Sequencing (RNA-seq) assays to identify DDX6-bound mRNAs. The expression and function of the DDX6 target genes in NSCLC were explored. Notably, we found that DDX6 bound to the CACHD1 transcript and increased its stability in NSCLC cells. CACHD1 was overexpressed in NSCLC tissues relative to normal lung tissues. Moreover, the CACHD1 upregulation was associated with advanced disease and reduced overall survival in NSCLC patients. Overexpression of CACHD1 accelerated the proliferation, colony formation, and invasion of NSCLC cells. Conversely, knockdown of CACHD1 suppressed DDX6-induced proliferation, invasion, and tumorigenesis of NSCLC cells. Further mechanistic investigation revealed that overexpression of DDX6 promoted the phosphorylation and activation of FAK in NSCLC cells, which relied on the presence of CACHD1. Chemical inhibition of FAK effectively reversed the aggressive phenotype of NSCLC cells induced by overexpression of DDX6 or CACHD1. Taken together, these findings support a crucial role for the DDX6/CACHD1/FAK axis in NSCLC progression. CACHD1 may represent a promising therapeutic target for NSCLC.