The Molecular Mechanism Of Human Helicase RecQL4 In Regulating Drug Resistance Of Gastric Cancer Cells

RecQL4, a member of RecQ helicase family with DNA-unwinding activity, participates in various DNA repair pathways, and its oncogenic potential was reported through its aberrantly elevated expression in various cancers. In this study, the prognostic and chemotherapeutic significance of RecQL4 in gastric cancer (GC) tissues and cells were investigated. We observed that 75%(15/20) of human GC tumor samples exhibited more than a 2.5-fold increase in RecQL4 mRNA expression relative to normal gastric tissues. In support, among 11 pairs of human primary GC and noncancerous controls,8 samples showed an increased level of RecQL4 protein, and a high level of RecQL4 staining was also observed in 80.4%(74/92) of primary human GC samples analyzed. Strikingly, tumors with a high RecQL4 expression correlated well with poor survival and GC cells with high RecQL4 expression showed resistance to cisplatin treatment. In support, we uncovered a novel role for RecQL4 in regulating the transcriptional activation of multidrug resistance gene MDR through its physical interaction with a transcription factor, Y-box binding protein 1 (YB1). Ectopic expression of RecQL4 in cisplatin-sensitive GC cells with low endogenous RecQL4 transformed them into cisplatin-resistance phenotype through a substantial elevation of YB1 phosphorylation and thereby MDR1 activation. Conversely, RecQL4 knock down in cisplatin-resistant GC cells with high endogenous RecQL4 not only suppressed YB1 phosphorylation but also dramatically reduced MDR1 induction leading to cisplatin sensitization. Our data clearly indicates that RecQL4 is a novel therapeutic target for GC and efficient RecQL4 mediated targeting of YB1-MDR1 pathway may be useful for GC treatment.