CDKN1A stabilizes Cyclin D3 by inhibiting its phosphorylation-dependent nuclear export following butyrate treatment

Butyrate-mediated inhibition of cell proliferation is part of the preventive role of dietary fiber against colorectal cancer (CRC). This effect notably involves the cyclin-dependent kinase inhibitor CDKN1A in human intestinal cells, yet the underlying molecular mechanisms remain incompletely understood. Previously, we observed a paradoxical increase in cyclin D3 (CCND3)—but not cyclin D1—levels upon butyrate exposure. Here, we demonstrate that the butyrate-induced accumulation of CCND3 results primarily from a CDKN1A-dependent stabilization, specifically extending its nuclear half-life. Proteomic analyses of CCND3 co-immunoprecipitates identified complexes involving CDKN1A, CDK4, CDK6, and the CRC-associated kinase CDK5, particularly enriched in butyrate-treated cells.