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

• DOI: 10.1371/journal.pone.0031431
• Publication Date: 2012-02-17T22:35:17Z
• Authors: Hongwu Zhu; Limin Xia; Yongguo Zhang; Honghong Wang; Wenjing Xu; Hao Hu; Jing Wang; Jing Xin; Yi Gang; Sumei Sha; Bin Xu; Daiming Fan; Yongzhan Nie; Kaichun Wu
• Keywords: Transcriptional Activation; 0301 basic medicine; ATP Binding Cassette Transporter, Subfamily B; Science; Molecular Sequence Data; Down-Regulation; Apoptosis; 03 medical and health sciences; Sirtuin 1; Stomach Neoplasms; Cell Line, Tumor; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; RNA, Small Interfering; Promoter Regions, Genetic; Base Sequence; Q; R; Activating Transcription Factor 4; Drug Resistance, Multiple; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Phenotype; Drug Resistance, Neoplasm; Medicine; Research Article; DNA Damage

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.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.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.