Gd-Metallofullerenol Nanomaterial Suppresses Pancreatic Cancer Metastasis by Inhibiting the Interaction of Histone Deacetylase 1 and Metastasis-Associated Protein 1

The treatment of pancreatic cancer frequently fails due to local recurrence and hepatic metastasis. Our previous study found that Gd@C(OH) can suppress pancreatic cancer by inhibiting MMP-2/9 expression. In this study, we further explored the epigenetic mechanism of Gd@C(OH) in human pancreatic cancer metastasis. Gd@C(OH) suppressed tumor metastasis through down-regulation of metastasis-associated protein 1 (MTA1), HDAC1, HIF-1α, and MMP-2/9 and up-regulation of reversion-cysteine protein with the Kazal motif (RECK). The level of acetylation was increased in the promoter region of the RECK gene after Gd@C(OH) treatment. The interaction of MTA1, HDAC1, and HIF-1α was inhibited by Gd@C(OH). Furthermore, large-scale molecular dynamics simulations revealed Gd@C(OH) could serve as an effective HDAC inhibitor to the protein-protein association between HDAC1 and MTA1, especially through MTA1 SANT and ELM2 dimerization domains. Our findings implicate Gd@C(OH) as a novel HDAC inhibitor acting to increase RECK expression by suppressing the MTA1/HDAC1 co-repressor complex. Gd@C(OH) 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@C(OH) activates RECK expression by inhibiting the interaction of HDAC1 and MTA1.