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

Abstract

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, and MMP-2/9 and up-regulation of reversion-cysteine protein with the <i>Kazal</i> motif (RECK). The level of acetylation was increased in the promoter region of the 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 could serve as an effective HDAC inhibitor to the protein–protein association between HDAC1 and MTA1, especially through MTA1’s SANT and ELM2 dimerization domains. Our findings implicate Gd@C₈₂(OH)₂₂ as a novel HDAC inhibitor acting to increase RECK expression by suppressing the MTA1/HDAC1 co-repressor complex. Gd@C₈₂(OH)₂₂ may serve as a potential HDAC1 inhibitor to suppress pancreatic cancer cell invasion and metastasis both <i>in vitro</i> and <i>in vivo</i>. According to computer analysis and experimental validation, Gd@C₈₂(OH)₂₂ activates RECK expression by inhibiting the interaction of HDAC1 and MTA1