American Chemical Society, ACS Nano, 7(9), p. 6826-6836, 2015
DOI: 10.1021/nn506782f
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The treatment of pancreatic cancer frequently fails due to local recurrence and hepatic metastasis. Our previous study found that Gd@C82(OH)22 can suppress pancreatic cancer by inhibiting MMP-2/9 expression. In this study, we further explored the epigenetic mechanism of Gd@C82(OH)22 in human pancreatic cancer metastasis. Gd@C82(OH)22 suppressed tumor metastasis through down-regulation of metastasis-associated protein 1 (MTA1), HDAC1, HIF-1α, MMP-2/9, and up-regulation of reversion-cysteine protein with Kazal motif (RECK). The level of acetylation was increased in the promoter region of RECK gene after Gd@C82(OH)22 treatment. The interaction of MTA1, HDAC1 and HIF-1α was inhibited by Gd@C82(OH)22. Furthermore, large-scale molecular-dynamics simulations revealed Gd@C82(OH)22 to serve as an effective HDAC inhibitor to the protein-protein association between HDAC1 and MTA1, especially through MTA1'sSANT and ELM2 dimerization domains. Our findings implicate Gd@C82(OH)22 as a novel HDAC inhibitor acting to increase RECK expression by suppressing MTA1/HDAC1 co-repressor complex. In conclusion, Gd@C82(OH)22 may serve as a potential HDAC1 inhibitor to suppress pancreatic cancer cell invasion and metastasis both in vitro and in vivo. According to computer analysis and experimental validation, Gd@C82(OH)22 activates RECK expression by inhibiting the interaction of HDAC1 and MTA1.