ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2. (28th July 2018)

• Record Type: Journal Article
• Authors: Luo, Qingyu; Wu, Xiaowei; Zhang, Yiping; Shu, Tong; Ding, Fang; Chen, Hongyan; Zhao, Pengfei; Chang, Wan; Zhu, Xiaolin; Liu, Zhihua
• Is Part Of: Cancer letters. Volume 427(2018)
• Page Start: 9
• Page End: 17
• Publication Date: 2018-07-28
• Subjects: ARID1A -- MRP2 -- Ovarian cancer -- Apoptosis -- Multiple drug resistance; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.04.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Multiple Drug Resistance (MDR) of ovarian cancer is a severe trouble for clinical treatment and always contributes to a bad prognosis. AT-rich interaction domain 1 A (ARID1A) has been recognized as a bona fide tumor suppressor gene in recent years, with the highest mutation rate in ovarian cancer. Previous study illustrated that ARID1A expression is negatively correlated with chemoresistance of ovarian cancer cases. However, the specific role of ARID1A in chemoresistance of ovarian cancer remains elusive. In this study, we showed that ARID1A knockdown in ovarian cancer cells significantly reduced their apoptosis rate and led to MDR, while ectopic expression of ARID1A showed opposite effects. ARID1A depletion transcriptionally activates the expression of multidrug resistance-associated protein 2 (MRP2) following chromatin remodeling. Furthermore, IHC analysis of ovarian cancer samples confirmed that ARID1A expression was strong negatively correlated with MRP2 expression. Both ARID1A and MRP2 expression levels are correlated with sensitivity to platinum. Collectively, our results illustrated that ARID1A loss in ovarian cancer leads to MDR through upregulation of MRP2, providing an opportunity to overcome the ARID1A loss induced chemoresistance of ovarian cancer by targeting MRP2. Highlights: ARID1A loss contributes to multiple drug resistance of ovarian cancer. ARID1A depletion activates MRP2 expression. ARID1A expression negatively correlates with MRP2 expression in ovarian cancer samples. MRP2 is a promising therapeutic target for ARID1A loss ovarian cancer patients.