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Abstract Background: Cisplatin (CDDP) is one of the standard treatment drugs for esophageal cancer (EC), but recurrence and metastasis are common due to intronic or acquired resistance. Research has shown that circRNAs may be involved in the regulattion of chemotherapy resistance. However, the underlying mechanism is still largely unknown. Methods: TE-1 (the human Esophageal Squamous Cell Carcinoma, ESCC) cell line that had acquired cisplatin resistance (TE-1/ CDDP) were established by means of the drug concentration gradient increasing method. The half maximal inhibitory concentration of cisplatin (IC50) and the biological characteristics of TE-1 and TE-1/CDDP cells were explored by CCK-8 assay, clone formation and transwell experiments. CircRNA microarray was utilized for identifying the gene expression patterns. Small interfering RNA was prepared to knock down the target gene and its biological effects on drug-resistant were observed. Western blotting was used to assess protein expression. Results: After 8 months, cisplatin resistant cell line was successfully established. CCK-8 assay indicated that TE-1/CDDP had 8.70fold increased IC50 in comparison with TE-1. Compared with TE-1, TE-1/CDDP cells displayed irregular morphology and exhibited stronger migration and invasion ability than its parental cells. cDNA microarray analysis shown that totally 410 circRNAs were Differentially Expressed (DE). 124 of which were up-regulated while the other 286 were down-regulated in the cisplatin resistant group. Among them, 191 DE host genes were identified, including 56 up-regulated and 135 down-regulated. Functional annotation revealed that the DE circRNAs were mainly involved in p53 signaling pathway, base excision repair, cellular carbon metabolism, Tricarboxylic Acid Cycle (TCA cycle) and propionate metabolism. Histone deacetylase-9 (HDAC9) was three-fold upregulated and was chosen as a cisplatin resistance host gene. Further experimental validation revealed that knockdown of HDAC9 could inhibit proliferation and invasion, as well as the protein expression of PAI-1, AKT, and ERK in TE-1/CDDP cells. HDAC9 appears to confer cisplatin resistance by targeting the AKT and ERK proteins. Conclusion: Our findings identified multiple aberrantly expressed circRNAs in cisplatin resistance EC cells that may provide a useful resource for identifying novel drug resistance associated circRNAs. The host gene HDAC9 participated in the regulation of cisplatin resistance and might be a therapeutic target in ESCC.
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