LncRNA PWAR6 regulates proliferation and migration by epigenetically silencing YAP1 in tumorigenesis of pancreatic ductal adenocarcinoma.

Abstract

Long non-coding RNAs (lncRNAs) are a novel class of regulators in multiple cancer biological processes. However, the functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. In this study, we identified PWAR6 as a frequently down-regulated lncRNA in PDAC samples as well as a panel of pancreatic cancer cell lines. Down-regulated PWAR6 was associated with multiple clinical outcomes, including advanced tumour stage, distant metastasis, and overall survival of PDAC patients. In our cell-based assays, ectopic expression of PWAR6 dramatically repressed PDAC cells proliferation, invasion and migration, accelerated apoptosis, and induced cell cycle arrest at G0/G1 phase. In contrast, depletion of PWAR6 mediated by siRNA exhibited opposite effects on PDAC cell behaviours. In vivo study further validated the anti-tumour role of PWAR6 in PDAC. By taking advantage of available online sources, we also identified YAP1 as a potential PWAR6 target gene. Negative correlation between YAP1 and PWAR6 expressions were observed in both online database and our PDAC samples. Notably, rescue experiments further indicated that YAP1 is an important downstream effector involved in PWAR6-mediated functions. Mechanistically, PWAR6 could bind to methyltransferase EZH2, a core component of Polycomb Repressive Complex 2 (PRC2) in regulating gene expression, and scaffold EZH2 to the promoter region of YAP1, resulting in epigenetic repression of YAP1. In conclusion, our data manifest the vital roles of PWAR6 in PDAC tumorigenesis and underscore the potential of PWAR6 as a promising target for PDAC diagnosis and therapy.

• Authors: Shanshan Huang, Yaqi Li, Jinhua Hu, Li Li, Zhen Liu, Hui Guo, Bailing Jiang, Jun Chen, Junhe Li, Xiaojun Xiang, Jun Deng, Jianping Xiong
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 9 Pg. 4275-4286 (05 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33834618 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Adaptor Proteins, Signal Transducing
• Biomarkers, Tumor
• RNA, Long Noncoding
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human

Topics

• Adaptor Proteins, Signal Transducing (antagonists & inhibitors, genetics, metabolism)
• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Pancreatic Ductal (genetics, metabolism, pathology)
• Cell Movement
• Cell Proliferation
• Epigenesis, Genetic
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Prognosis
• RNA, Long Noncoding (genetics)
• Survival Rate
• Transcription Factors (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• YAP-Signaling Proteins