Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway
Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253121002717 |
| _version_ | 1818834971942453248 |
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| author | Weicheng Liang Chuanjian Shi Weilong Hong Panlong Li Xue Zhou Weiming Fu Lizhu Lin Jinfang Zhang |
| author_facet | Weicheng Liang Chuanjian Shi Weilong Hong Panlong Li Xue Zhou Weiming Fu Lizhu Lin Jinfang Zhang |
| author_sort | Weicheng Liang |
| collection | DOAJ |
| description | Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer. |
| first_indexed | 2024-12-19T02:43:18Z |
| format | Article |
| id | doaj.art-853ac58ab0e4400bb591a305f25bf75f |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-19T02:43:18Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-853ac58ab0e4400bb591a305f25bf75f2022-12-21T20:39:03ZengElsevierMolecular Therapy: Nucleic Acids2162-25312021-12-012613511363Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathwayWeicheng Liang0Chuanjian Shi1Weilong Hong2Panlong Li3Xue Zhou4Weiming Fu5Lizhu Lin6Jinfang Zhang7Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China; Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. ChinaDepartment of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. ChinaBiotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. ChinaDepartment of Ultrasonic Medicine, Guangzhou Women and Children's Medical Center, Guangzhou, P.R. ChinaSchool of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. ChinaDepartment of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P.R. China; Corresponding author: Li-Zhu Lin, Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China; Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China; Corresponding author: Jin-Fang Zhang, Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.Aberrant expression of long non-coding RNAs (lncRNAs) has been reported in multiple cancers. However, the underlying mechanisms mediated by super-enhancers remain elusive. Here we sought to define the role of a novel lncRNA termed lncRNA-DAW in tumorigenesis. Our results revealed that lncRNA-DAW was driven by a liver-specific super-enhancer and transcriptionally activated by HNF4G, leading to frequent elevation in hepatocellular carcinoma (HCC) specimens. Ectopic expression of lncRNA-DAW promoted both in vivo and in vitro tumor growth. By using RNA sequencing, Wnt2 was screened out as a downstream effector of lncRNA-DAW. We next found that lncRNA-DAW physically interacted with EZH2, a negative regulator of Wnt2. This interplay subsequently potentiated CDK1-EZH2 interaction, leading to the phosphorylation and ubiquitination of EZH2. The lncRNA-DAW-mediated EZH2 degradation facilitated the de-repression of Wnt2 transcription, which eventually activated the Wnt/β-catenin pathway. Furthermore, we verified that Wnt2 potentiated in vitro and in vivo cancer cell growth by activating the Wnt/β-catenin pathway. Finally, Wnt2 amplification was confirmed as a common event in liver cancer, and the expression of lncRNA-DAW was positively correlated with Wnt2 in HCC specimens. Collectively, we are the first to identify lncRNA-DAW as a novel candidate oncogene in liver cancer, and this lncRNA may serve as a novel clinical diagnosis biomarker for liver cancer.http://www.sciencedirect.com/science/article/pii/S2162253121002717cell growthlncRNAsuper-enhancerWnt/β-catenin pathwayliver cancer |
| spellingShingle | Weicheng Liang Chuanjian Shi Weilong Hong Panlong Li Xue Zhou Weiming Fu Lizhu Lin Jinfang Zhang Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway Molecular Therapy: Nucleic Acids cell growth lncRNA super-enhancer Wnt/β-catenin pathway liver cancer |
| title | Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway |
| title_full | Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway |
| title_fullStr | Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway |
| title_full_unstemmed | Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway |
| title_short | Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway |
| title_sort | super enhancer driven lncrna daw promotes liver cancer cell proliferation through activation of wnt β catenin pathway |
| topic | cell growth lncRNA super-enhancer Wnt/β-catenin pathway liver cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2162253121002717 |
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