A conformation-sensitive product inhibitor of HDAC1/2 potentiates WNT signaling.

Abstract

Pharmacological enhancement of WNT/β-catenin signaling holds promises for tissue repair and regeneration. Here, we identify WNA1, an isoxazole-based small molecule, as a potent activator of WNT/β-catenin signaling. WNA1 stimulates β-catenin signaling in WNT-dependent manner and promotes skin hair growth in vivo. 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 WNA1 enhances β-catenin signaling by selectively inhibiting HDAC1/2. Structural and biochemical analyses reveal that WNA1 is hydrolyzed by the HDAC1-MTA1 complex and its product is trapped in the foot pocket of HDAC1 in an inositol-hexaphosphate-dependent manner. HDAC1 mutants with reduced foot pocket abrogate WNA1-induced histone acetylation and β-catenin accumulation. These findings establish WNA1 as a conformation-sensitive, foot-pocket-anchored product inhibitor selectively targeting complex-bound HDAC1/2 and reveal a unique mechanism for HDAC1/2 inhibition and WNT potentiation.

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