Chidamide and Oxaliplatin Synergistically Inhibit Colorectal Cancer Growth by Regulating the RPS27A-MDM2-P53 Axis

Abstract

Zhaopeng Li,1,* Deyong Bu,1,* Xiaobin Wang,1 Lin Zhu,2 Daoyan Lei,3 Fengling Tang,1 Xianghua Sun,1 Cheng Chen,4 Xiang Ji,5 Song Bai1 1Department of Geriatric General Surgery, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650000, People’s Republic of China; 2Department of Ultrasound, the Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China; 3Department of Ultrasound, Jiangchuan District People’s Hospital, Yuxi, Yunnan, 652600, People’s Republic of China; 4Department of Breast Surgery, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650000, People’s Republic of China; 5Department of Day Surgery, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Deyong Bu; Song Bai, Department of Geriatric General Surgery, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650000, People’s Republic of China, Tel/Fax [phone], Email [email protected]; [email protected]: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism.Material and Methods: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidamide and oxaliplatin monotherapy and the combined treatment on cell proliferation, invasion, migration, and apoptosis were detected. Third, whole-transcriptome RNA sequencing (RNA-seq) was performed to seek the potential targeted gene by which chidamide plus oxaliplatin exerted anti-tumor effects. Fourth, the validation of the targeted gene and the signal pathway it regulated were performed. Finally, the anti-tumor effect of chidamide plus oxaliplatin on mice xenograft was examined.Results: Chidamide and oxaliplatin acted synergistically to inhibit CRC growth in vitro and in vivo (CI< 1). Besides, compared with oxaliplatin monotherapy, chidamide could significantly enhance oxaliplatin-induced inhibition in cell proliferation, invasion, and migration, and promotion in HCT-116 and RKO cell apoptosis (P< 0.05). The RNA-seq displayed that, compared to oxaliplatin monotherapy, RPS27A mRNA was evidently decreased in HCT-116 cells treated with chidamide plus oxaliplatin (P< 0.001). Then, we found RPS27A was highly expressed in CRC tissues and CRC cell lines (P< 0.001). Silence of RPS27A attenuated proliferation and induced apoptosis in HCT-116 and RKO cells via downregulation of MDM2 expression and upregulation of P53. Next, RPS27A overexpression could partially reverse chidamide plus oxaliplatin induced growth inhibition and apoptosis in HCT-116 and RKO cells (P< 0.01). RPS27A overexpression could promote the upregulation of MDM2 and downregulation of P53 after the combined treatment of chidamide with oxaliplatin.Conclusion: Chidamide and oxaliplatin acted synergistically to suppress CRC growth by the inhibition of the RPS27A-MDM2-p53 axis.Keywords: chidamide, oxaliplatin, colorectal cancer, synergism

Keywords

• chidamide
• oxaliplatin
• colorectal cancer
• synergism