Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway

Weicheng Liang; Chuanjian Shi; Weilong Hong; Panlong Li; Xue Zhou; Weiming Fu; Lizhu Lin; Jinfang Zhang

doi:10.1016/j.omtn.2021.10.028

Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway

Mol Ther Nucleic Acids. 2021 Nov 3:26:1351-1363. doi: 10.1016/j.omtn.2021.10.028. eCollection 2021 Dec 3.

Authors

Weicheng Liang^{1

2}, Chuanjian Shi^{3

4}, Weilong Hong⁵, Panlong Li², Xue Zhou⁶, Weiming Fu^{3

4}, Lizhu Lin⁷, Jinfang Zhang^{1

8}

Affiliations

¹ Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
² Biotherapy Centre, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
³ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China.
⁴ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P.R. China.
⁵ Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
⁶ Department of Ultrasonic Medicine, Guangzhou Women and Children's Medical Center, Guangzhou, P.R. China.
⁷ Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P.R. China.
⁸ 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.

Abstract

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.

Keywords: Wnt/β-catenin pathway; cell growth; liver cancer; lncRNA; super-enhancer.