title: 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 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.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Pan
authors.affiliation: ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.affiliation: §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States.
authors.forename: Seung-gu
authors.initials: SG
authors.lastname: Kang
authors.forename: Youyong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: ⊥Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Soochow University, Suzhou 215123, China.
authors.forename: Zaixing
authors.initials: Z
authors.lastname: Yang
authors.affiliation: §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States.
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.affiliation: ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
authors.affiliation: §Computational Biology Center, IBM Thomas J. Watson Research Center,1101 Kitchawan Road, Yorktown Heights, New York 10598, United States.|⊥Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Soochow University, Suzhou 215123, China.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
authors.affiliation: ‡CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology and Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100190, China.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D037741:Fullerenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005682:Gadolinium / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators
chemical_list: D000970:Antineoplastic Agents; D037741:Fullerenes; D058851:GPI-Linked Proteins; C000608549:Gd@C82(OH)22; C089320:MTA1 protein, human; C115460:RECK protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D005682:Gadolinium; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
keywords: Gd@C82(OH)22; HDAC1; HIF-1α; MTA1; RECK; metastasis; pancreatic cancer