Aucubin inhibits epithelial-mesenchymal transition and angiogenesis in colorectal cancer via the HDAC6/PI3K/Akt signaling pathway.

Colorectal cancer (CRC) represents a prevalent malignancy worldwide, with its high incidence and mortality rates necessitating novel therapeutic strategies. Aucubin (AU), a natural compound, has demonstrated diverse biological activities, yet its role and mechanisms in CRC remain incompletely understood. The effects of AU on the malignant biological behaviors of CRC were evaluated by CCK-8 assay, colony formation, Transwell, tube formation, wound healing, and flow cytometry experiments. ELISA quantification of angiogenic markers (MMP-2, MMP-9, VEGFA), immunofluorescence detection of epithelial-mesenchymal transition (EMT) markers (E-cadherin/N-cadherin) and key pathway protein (HDAC6), alongside Western blot assessment of EMT-related proteins, angiogenesis factors, and HDAC6/PI3K/Akt pathway components (HDAC6, p-PI3K/PI3K, p-AKT/AKT). Mechanistic investigations employed HDAC6-overexpressing and knockdown cell models. In vivo, HCT116 xenograft models were established for tumor volume/weight measurements, immunohistochemistry, HE staining, TUNEL assays, and Western blot validation. In vitro, AU significantly suppressed HCT116/SW620 cell proliferation, migration, and invasion while promoting apoptosis. AU reversed EMT phenotypes via E-cadherin upregulation and N-cadherin/Vimentin/Snail downregulation, concurrently inhibiting MMP-2/9 activity. AU impaired HUVEC tube formation and reduced VEGFA/FGF2/PDGF-BB expression. Mechanistically, AU inhibited HDAC6 expression and PI3K/Akt phosphorylation. HDAC6 overexpression partially rescued AU's effects, whereas HDAC6 knockdown potentiated them. In vivo results corroborated these findings, showing suppressed tumor growth, reduced Ki-67 expression, improved histopathology, enhanced apoptosis, and modulated expression of EMT/angiogenesis/HDAC6/PI3K/Akt pathway proteins. This study demonstrates that AU exerts antitumor effects by suppressing EMT and angiogenesis through HDAC6/PI3K/Akt pathway inhibition. Clinical trial number: not applicable.