Activation of multidrug-resistance gene (MDR1) is one of main reasons responsible for clinical treatment failure and recurrence in cancer patients. However, the detailed molecular mechanism in MDR1 activation is not well-understood.

Using gastric cancer cells as model, the studies of Dr. ZHAO Yongliang’s group from Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences revealed that the human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway. The work has been published online in Cancer Research on March 24.

RecQL4 as a member of RecQ helicase family with DNA-unwinding activity plays an important role in maintaining the stability of nuclear and mitochondrial genomes. The previous reports from Dr. ZHAO and other groups demonstrated that elevated RecQL4 expression was a frequent event in a variety of human cancers including gastric, breast and prostate cancer, etc. However, its prognostic and chemotherapeutic significance are not known. Using gastric cancer as model, Dr. ZHAO’s group found that gastric tumors with high RecQL4 expression correlated well with poor survival and GC lines with high RecQL4 expression displayed increased resistance to cisplatin treatment.

Consistently, they uncovered a novel role for RecQL4 in the transcriptional regulation of multidrug resistance gene (MDR1) 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 substantially reduced MDR1 induction leading to cisplatin sensitization. Their data clearly indicates that RecQL4 is a novel therapeutic target for GC and efficient RecQL4 mediated targeting of Akt-YB1-MDR1 axis may be useful for GC treatment.

This work was supported by the National Basic Research Program of China , the National Natural Science Foundation of China and CAS Key Research program.

RECQL4 expression level affects sensitivity to cisplatin treatment (left), and altered sensitivity to cisplatin by modulating RECQL4 expression (right). (Image by ZHAO Yongliang's group)