Repression of the Long Noncoding RNA-LET by Histone Deacetylase 3 Contributes to Hypoxia-Mediated Metastasis

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