Piroctone olamine promotes BECN1 transcription and activates autophagy by targeting HDAC6 in colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, often diagnosed at advanced stages when treatment options are limited. Histone deacetylases (HDACs) are frequently overexpressed in CRC, promoting tumor cell proliferation and survival through epigenetic regulation. In the current study, we identified piroctone olamine (PO), an antifungal agent, as a novel inhibitor of CRC cell proliferation which simultaneously activates autophagy to promote CRC cell death with minimal cytotoxicity to normal cells. Inhibition of autophagy completely abolished PO-induced cell death, confirming that autophagy is the primary pathway for cell death. Transcriptomic analysis revealed that PO significantly upregulated the expression of beclin-1 (BECN1), an essential autophagy-related gene. Structural analysis indicated that PO contains an oxime group, structurally similar to hydroxamate-based HDAC inhibitors. We also found that PO specifically targeted and inhibited HDAC6, leading to increased acetylation of histone H3 at lysine 9 (H3K9ac). The increase in H3K9ac promoted the binding of transcription factors at the BECN1 promoter, enhancing BECN1 transcription, as confirmed by ChIP-qPCR and dual-luciferase assays. In vivo, PO effectively reduced HDAC6 expression, elevated BECN1 levels, promoted autophagy, suppressed tumor growth in a syngeneic mouse CRC model. In conclusion, PO selectively inhibits HDAC6, promotes histone acetylation at H3K9, upregulates BECN1 expression, and induces autophagy-dependent cell death in CRC cells. These findings position PO as a promising candidate for the development of HDAC6-targeted therapies in CRC.