Here, HNF4α is identified as a direct transcriptional repressor of the HOTAIR gene in epithelial cells by studying (i) in vitro hepatocyte cells able to undergo EMT/MET dynamics [10, 24–26], (ii) an in vivo model of hepatocyte-specific Hnf4α knockout (Hnf4aF/F;AlbERT2cre mice [27]), and (iii) colon cancer cells representative of different states of tumor progression [28]. This evidence concerns the gene HNF4A and malignant colon neoplasm.