Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis

Mol Cell. 2013 Mar 28;49(6):1083-96. doi: 10.1016/j.molcel.2013.01.010. Epub 2013 Feb 7.


Recently, long noncoding RNAs (lncRNAs) were found to be dysregulated in a variety of tumors. However, it remains unknown how and through what molecular mechanisms the expression of lncRNAs is controlled. In this study, we found that the lncRNA Low Expression in Tumor (lncRNA-LET) was generally downregulated in hepatocellular carcinomas, colorectal cancers, and squamous-cell lung carcinomas. We demonstrated that hypoxia-induced histone deacetylase 3 repressed lncRNA-LET by reducing the histone acetylation-mediated modulation of the lncRNA-LET promoter region. Interestingly, the downregulation of lncRNA-LET was found to be a key step in the stabilization of nuclear factor 90 protein, which leads to hypoxia-induced cancer cell invasion. Moreover, the relationship among hypoxia, histone acetylation disorder, low lncRNA-LET expression level, and metastasis was found in clinical hepatocellular carcinoma samples. These results advance our understanding of the role of lncRNA-LET as a regulator of hypoxia signaling and offer new avenues for therapeutic intervention against cancer progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Base Sequence
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / secondary*
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Movement
  • Down-Regulation
  • Female
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • Histone Deacetylases / physiology*
  • Histones / metabolism
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / secondary*
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Nuclear Factor 90 Proteins / genetics
  • Nuclear Factor 90 Proteins / metabolism
  • Protein Processing, Post-Translational
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism


  • Histones
  • ILF3 protein, human
  • Nuclear Factor 90 Proteins
  • RNA, Long Noncoding
  • Histone Deacetylases
  • histone deacetylase 3