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Genome-Wide Screening and Functional Analysis Identifies Tumor Suppressor Long Noncoding RNAs Epigenetically Silenced

Feiyue Xu1, Chi Han Li1, Chi Hin Wong1

  • 1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

Cancer Research
|February 6, 2019
PubMed

Insights

Two long noncoding RNAs (lncRNAs), TCAM1P-004 and RP11-598D14.1, act as tumor suppressors in hepatocellular carcinoma (HCC). They are epigenetically silenced by EZH2, and their loss promotes HCC growth, suggesting EZH2 as a therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Long noncoding RNAs (lncRNAs) are implicated in cancer development, but their specific roles and regulatory mechanisms in hepatocellular carcinoma (HCC) are not fully understood.
  • Deregulation of lncRNAs, particularly their downregulation, is a common event in cancer progression.

Purpose of the Study:

  • To investigate the function of frequently downregulated lncRNAs in HCC.
  • To elucidate the epigenetic mechanisms responsible for lncRNA deregulation in HCC.
  • To identify potential therapeutic targets for HCC treatment.

Main Methods:

  • Quantitative analysis of lncRNA expression in HCC tumors and adjacent normal tissues.
  • Chromatin immunoprecipitation (ChIP) assays to assess histone modifications (H3K27me3) at lncRNA promoters.
  • In vitro and in vivo assays to evaluate the tumor-suppressive functions of lncRNAs.
  • RNA pull-down assays coupled with mass spectrometry to identify lncRNA-protein interactions.
  • Analysis of signaling pathways regulated by lncRNA-protein complexes.

Main Results:

  • TCAM1P-004 and RP11-598D14.1 were significantly downregulated in HCC tissues.
  • EZH2-mediated H3K27 trimethylation at the promoters of TCAM1P-004 and RP11-598D14.1 led to their silencing.
  • Both lncRNAs exhibited tumor-suppressive activities by inhibiting cell growth, survival, and transformation in HCC.
  • TCAM1P-004 interacted with IGF2BP1 and HIST1H1C; RP11-598D14.1 interacted with IGF2BP1 and STAU1.
  • These interactions were crucial for regulating proliferation-associated pathways (p53, MAPK, HIF1α).
  • Overexpression of EZH2 correlated with repression of these lncRNAs and promoted HCC progression.

Conclusions:

  • TCAM1P-004 and RP11-598D14.1 function as tumor suppressors in HCC by forming complexes with specific proteins.
  • Epigenetic silencing of these lncRNAs by EZH2 contributes to HCC development and progression.
  • Targeting EZH2 may represent a viable therapeutic strategy for HCC.

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