A conformation-sensitive product inhibitor of HDAC1/2 potentiates WNT/β-catenin signaling [ChIP-seq II]

Here, we identify WNA1, an isoxazole-based small molecule, as a potent activator of WNT/β-catenin signaling. WNA1 stimulates β-catenin signaling in different cellular contexts, and this activity requires production of endogenous WNT.

In vivo, WNA1 promotes skin hair growth, consistent with the established role of β-catenin signaling in hair follicle development. Intriguingly, WNA1 increases histone acetylation with minimal activity on uncomplexed recombinant histone deacetylases (HDACs), while conventional HDAC inhibitors exhibit minimal β-catenin-stabilizing activity. We demonstrate that β-catenin signaling is repressed by the HDAC1/2-containing NuRD complex, and that WNA1 enhances β-catenin signaling through selectively inhibiting HDAC1/2.