Gd–metallofullerenol nanomaterial suppresses pancreatic cancer metastasis by inhibiting the interaction of histone deacetylase 1 and metastasis-associated protein 1

Y Pan, L Wang, S Kang, Y Lu, Z Yang, T Huynh… - Acs Nano, 2015 - ACS Publications
Y Pan, L Wang, S Kang, Y Lu, Z Yang, T Huynh, C Chen, R Zhou, M Guo, Y Zhao
Acs Nano, 2015ACS Publications
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 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 Kazal 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 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.
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