Activating Transcription Factor 4 Confers a Multidrug Resistance Phenotype to Gastric Cancer Cells through Transactivation of SIRT1 Expression

BACKGROUND: Multidrug resistance (MDR) in gastric cancer remains a major challenge to clinical treatment. Activating transcription factor 4 (ATF4) is a stress response gene involved in homeostasis and cellular protection. However, the expression and function of ATF4 in gastric cancer MDR remains unknown. In this study, we investigate whether ATF4 play a role in gastric cancer MDR and its potential mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that ATF4 overexpression confered the MDR phenotype to gastric cancer cells, while knockdown of ATF4 in the MDR variants induced re-sensitization. In this study we also showed that the NAD(+)-dependent histone deacetylase SIRT1 was required for ATF4-induced MDR effect in gastric cancer cells. We demonstrated that ATF4 facilitated MDR in gastric cancer cells through direct binding to the SIRT1 promoter, resulting in SIRT1 up-regulation. Significantly, inhibition of SIRT1 by small interfering RNA (siRNA) or a specific inhibitor (EX-527) reintroduced therapeutic sensitivity. Also, an increased Bcl-2/Bax ratio and MDR1 expression level were found in ATF4-overexpressing cells. CONCLUSIONS/SIGNIFICANCE: We showed that ATF4 had a key role in the regulation of MDR in gastric cancer cells in response to chemotherapy and these findings suggest that targeting ATF4 could relieve therapeutic resistance in gastric cancer.