title: Downregulation of YEATS4 by miR-218 sensitizes colorectal cancer cells to L-OHP-induced cell apoptosis by inhibiting cytoprotective autophagy.
abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Deregulation of microRNAs (miRNAs) has been reported to participate in CRC progression. In the present study, we observed downregulation of miR-218 and upregulation of YEATS domain containing 4 (YEATS4) in CRC tissues and in multidrug-resistant HCT-116/L-OHP cells compared with these levels in normal tissues and parental HCT-116 cells, respectively. The results indicated that miR-218 overexpression significantly decreased the IC50 value of oxaliplatin (L-OHP) in the HCT-116/L-OHP cells, and suppression of miR-218 significantly enhanced the IC50 of L-OHP in the HCT-116 cells. Flow cytometric analysis showed that miR-218 overexpression alone promoted cell apoptosis in the HCT-116/L-OHP cells, which was further enhanced in response to L-OHP, and miR-218 inhibition decreased cell apoptosis in the HCT-116 cells following treatment with L-OHP. Western blot analysis indicated that, compared with the small increase observed in HCT-116 cells, the relative LC3 II level in HCT-116/L-OHP cells after lysosome inhibition via chloroquine (CQ) was markedly upregulated following L-OHP treatment, suggesting induction of autophagy. Exposure of HCT-116/L-OHP cells to L-OHP after control mimic transfection increased autophagic flux, as reflected by increased LC3 II levels, while miR-218 overexpression partly reversed L-OHP-mediated LC3 II accumulation. Additionally, both miR-218 overexpression and CQ treatment promoted L-OHP-induced HCT-116/L-OHP cell apoptosis. Molecularly, our results confirmed that miR-218 directly targets the YEATS4 gene and inhibits YEATS4 expression. Furthermore, YEATS4 overexpression without the 3'-untranslated region (3'-UTR) restored miR-218-inhibited YEATS4 and LC3 II expression, and abolished miR-218-stimulated cell viability loss and cell apoptosis increase in response to L-OHP. In conclusion, miR-218 sensitized HCT-116/L-OHP cells to L-OHP-induced cell apoptosis via inhibition of cytoprotective autophagy by targeting YEATS4 expression.
authors: Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Qiang
authors: Q
authors: Fu
authors: Department of Medical Oncology, Zhengzhou Central Hospital (The Affiliated Central Hospital of Zhengzhou University), Zhengzhou, Henan 450007, P.R. China.
authors: Jing
authors: J
authors: Cheng
authors: Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Jindai
authors: J
authors: Zhang
authors: Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Yonglei
authors: Y
authors: Zhang
authors: Department of Digestive Oncology, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Xiaobing
authors: X
authors: Chen
authors: Department of Gastrointestinal Surgery, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Jianguo
authors: J
authors: Xie
authors: Department of Digestive Oncology, Tumor Hospital of Henan Province (The Affiliated Tumor Hospital of Zhengzhou University), Zhengzhou, Henan 450008, P.R. China.
authors: Suxia
authors: S
authors: Luo
mesh_terms: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001483:Base Sequence; D001665:Binding Sites; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019610:Cytoprotection; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D014157:Transcription Factors; C109446:YEATS4 protein, human; D000077150:Oxaliplatin