HOXA5 Promotes Differentiation by Reducing WNT Signaling

In colorectal cancer, a small population of self-renewing cancer stem cells (CSC) is an important driver of metastasis and is more resistant to treatment than differentiated cells. In normal intestinal epithelium, WNT/β-catenin signaling controls the maintenance of the stem cell population. In order to identify potential therapeutic strategies to target colorectal CSCs, Ordóñez-Morán and colleagues investigated the role of WNTs in maintaining their stem-cell properties. In normal intestinal epithelium, genetic ablation of WNT signaling promoted the terminal differentiation of stem cells, and transcriptional profiling determined that homeobox A5 (HOXA5) expression was inversely correlated with WNT signaling and expression of WNT target genes. HOXA5 inhibited intestinal stem cell maintenance and was required for terminal differentiation. In a human colon cancer dataset, HOXA5 expression was lower in carcinoma than in normal colon tissue, and high HOXA5 expression was an independent prognostic factor predicting improved relapse-free survival. WNT signaling suppressed HOXA5 expression indirectly via WNT-mediated upregulation of MYC and repression by the MYC–MIZ1 complex. Stable expression of HOXA5 in colon cancer cell lines promoted terminal differentiation and overcame WNT-driven transformation, suggesting inhibition of stem-cell traits, and, in vivo, HOXA5 reduced the growth and metastatic progression of tumor xenografts. In addition, HOXA5 reciprocally repressed WNT signaling, providing a mechanism by which HOXA5 inhibits the stem cell phenotype. Treatment of colon cancer cells with retinoids such as all-trans retinoic acid, which have been shown to upregulate HOXA5 in breast cancer, promoted CSC differentiation and blocked colon cancer initiation, progression, and metastasis via HOXA5 induction. These results demonstrate that WNT and HOXA5 negatively regulate each other to control tumor cell differentiation, and suggest that retinoids may have promise in treating colorectal cancer by promoting loss of the CSC phenotype.

Ordóñez-Morán P, Dafflon C, Imajo M, Nishida E, Huelsken J. HOXA5 counteracts stem cell traits by inhibiting Wnt signaling in colorectal cancer. Cancer Cell 2015;28:815–29.