Polydatin upregulates ZDHHC19 to promote apoptosis of acute myeloid leukemia cells via mediating BID palmitoylation.

BACKGROUND: Polydatin, extracted from Polygonum cuspidatum, has been demonstrated to exert anti-tumor effects and induce apoptosis in several cancers including acute myeloid leukemia (AML). This study explored the potential mechanism of polydatin regulating apoptosis in AML. However, its precise molecular mechanism in AML remains poorly understood. METHODS: Patients with AML or non-malignant hematological disease were recruited for collecting bone marrow samples. In AML cell lines, cell viability and apoptosis were determined with CCK-8 and flow cytometry, respectively. The palmitoylation level of BH3 interacting-domain death agonist (BID) was assessed using Acyl-RAC assay. The interaction between BID and zinc finger DHHC-type palmitoyltransferase 19 (ZDHHC19) was validated by co-immunoprecipitation. Western blot and immunofluorescence were used for measuring protein expression and localization. The role of polydatin in vivo was confirmed by establishing a xenograft model with nude mice, while Ki67 expression and apoptosis in tumors were measured with immunohistochemistry and TUNEL assay. RESULTS: ZDHHC19 and BID palmitoylation were decreased in AML patients and cell lines. In HL-60 and MOLM-13 cells, polydatin treatment reduced cell viability, promoted apoptosis, and increased apoptosis-related proteins including BID, caspase-8, and cytochrome C. BID-cysteine (C)3/15-WT, but not BID-C3/15-Mut, led to increased BID palmitoylation and mitochondrial translocation. Polydatin treatment facilitated BID palmitoylation and apoptosis, when overexpressing BID-C3/15-WT but not BID-C3/15-Mut. The combination and co-localization of ZDHHC19 and BID were confirmed in AML cells. The effects of polydatin on promoting apoptosis and inhibiting tumor growth in vitro and in vivo were antagonized when silencing ZDHHC19. CONCLUSION: This study reveals a novel mechanism by which polydatin promotes apoptosis in AML through ZDHHC19-mediated BID palmitoylation. These findings suggest that polydatin may serve as a promising therapeutic candidate targeting apoptosis in AML.