Integrative epigenomic-transcriptomic analyses of hypoxia-induced epithelial–mesenchymal transition reveal a 30-gene panel associated with metastasis in non-small cell lung cancer

As a critical feature of the tumor microenvironment, hypoxia is known as a potent inducer of tumor metastasis, and it has been proposed that the initial steps in metastasis involve an epithelial–mesenchymal transition (EMT) process. Given a strong correlation among hypoxia, EMT and metastasis, an integrative assessment of gene expression and DNA modification program of hypoxia-induced EMT via high-throughput sequencing technologies will provide an increased understanding of the molecular basis of tumor invasion and metastasis. Here, we present the genome-wide transcriptional and epigenetic profiles of non-small cell lung cancer (NSCLC) cells under normoxic and hypoxic conditions. We demonstrate that hypoxia induces EMT along with dynamic alterations of transcriptional expression and epigenetic modifications in both A549 and HCC827 cells. After trained on the dataset of patients with invasive and non-invasive lung adenocarcinomas, a characteristic 30-gene panel was identified, consisting of genes involved in EMT, hypoxia response, glycometabolism and epigenetic modifications. In particular, this panel clearly stratified NSCLC patients with significant differences in overall survival across three independent datasets. Therefore, the 30-gene signature can preferentially be valuable as combined biomarkers for prediction of metastasis and prognostic stratification in patients with NSCLC.