PCAT‐1 contributes to cisplatin resistance in gastric cancer through epigenetically silencing PTEN via recruiting EZH2

• Published in: Journal of cellular biochemistry Vol. 121; no. 2; pp. 1353 - 1361
• Main Authors: Li, Hui, Ma, Xuhui, Yang, Desheng, Suo, Zhimin, Dai, Rujiang, Liu, Chunhong
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2020
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Movement; Cell Proliferation; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Drug Resistance, Neoplasm - genetics; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; EZH2; Gastric cancer; Gene Expression Regulation, Neoplastic; Histone methyltransferase; Homology; Humans; lncRNA PCAT‐1; Prostate cancer; PTEN; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Sensitivity enhancement; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Transcription; Tumor cell lines; Tumor Cells, Cultured; PTEN; gastric cancer; cisplatin; lncRNA PCAT-1; EZH2
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.29370

The aim of this study was to investigate the functional role and the underlying molecular mechanism of long noncoding RNA (lncRNA) prostate cancer–associated transcript 1 (PCAT‐1) in cisplatin resistance of gastric cancer (GC). Our results indicated that PCAT‐1 was overexpressed in CDDP‐resistant GC tumor tissues and cell lines. High expression of PCAT‐1 was closely correlated with short overall survival in patients with GC. Downregulation of PCAT‐1 resensitized CDDP‐resistant GC cells to cisplatin. In addition, PCAT‐1 epigenetically silenced PTEN through binding to the histone methyltransferase enhancer of zeste homolog 2 (EZH2), thus increasing H3K27me3. More importantly, PTEN silencing counteracted PCAT‐1 knockdown–mediated enhancement in cisplatin sensitivity of CDDP‐resistant GC cells. In summary, PCAT‐1 led to cisplatin resistance in GC cells through epigenetically suppressing PTEN expression, providing a novel therapeutic strategy for GC patients with chemoresistance. In this study, we found that PCAT‐1 was upregulated in gastric cancer (GC) tissues from The Cancer Genome Atlas (TCGA) datasets and CDDP‐resistant GC tissues and cells. In addition, knockdown of PCAT‐1 resensitized CDDP‐resistant GC cells to CDDP. Notably, our study demonstrated an epigenetically regulatory mechanism between PCAT‐1 and PTEN, which conferred CDDP resistance in GC, which provided theoretical basis for identification of potential therapeutic targets in GC chemoresistance.