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

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 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. 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 InsP6-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 that selectively targets complex-bound HDAC1/2. Our study reveals a unique mechanism for HDAC1/2 inhibition and WNT potentiation, paving the way for therapeutic applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328958 | GEO | 2026/09/01

REPOSITORIES: GEO

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

Project description: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 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. 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 InsP6-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 that selectively targets complex-bound HDAC1/2. Our study reveals a unique mechanism for HDAC1/2 inhibition and WNT potentiation, paving the way for therapeutic applications.

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

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Expression data from human hair follicles (ex vivo) incubated with cyclosporine A and vehicle control

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The TRIP12 E3 Ligase Induces Interaction Between the SWI/SNF Component BRG1 and Beta-catenin to Promote Wnt Signaling

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