HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer

Hierarchical organization of tissues relies on stem cells, which either self-renew or produce committed progenitors predestined for lineage differentiation. Here we identify HOXA5 as an important repressor of intestinal stem cell fate in vivo and identify a reciprocal feedback between HOXA5 and Wnt signaling. HOXA5 is suppressed by the Wnt pathway to maintain stemness and becomes active only outside the intestinal crypt where it inhibits Wnt signaling to enforce differentiation. In colon cancer, HOXA5 is downregulated, and its re-expression induces loss of the cancer stem cell phenotype, preventing tumor progression and metastasis. Tumor regression by HOXA5 induction can be triggered by retinoids, which represent tangible means to treat colon cancer by eliminating cancer stem cells. [Display omitted] •Wnt and HOXA5 exert mutual antagonism to control intestinal stem cell fate•Induction of HOXA5 eliminates cancer stem cells and prevents metastasis•Retinoid differentiation therapy acts via HOXA5 to block colon cancer progression•Retinal acts preferentially on ALDH1+ stem cells to induce differentiation Ordóñez-Morán et al. demonstrate a mutual negative regulation between Wnt signaling and HOXA5 expression in controlling intestinal stem cell maintenance and differentiation. HOXA5 expression is reduced in colon cancer but, importantly, can be activated by retinoids to inhibit tumor progression and metastasis.