title: Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer.
abstract: Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and Apc(Min/+) CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC.
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Tzu-Tang
authors.initials: TT
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Wen-Shu
authors.initials: WS
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Ping
authors.initials: P
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan; Department of Oncology, National Taiwan University Hospital, Taipei 106, Taiwan; Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City 220, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan; Department of Pathology, National Taiwan University Hospital, Taipei 106, Taiwan.
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan; Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Jhih-Bin
authors.initials: JB
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Nai-Wei
authors.initials: NW
authors.lastname: Chen
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, Taiwan.
authors.forename: Ming-Shiang
authors.initials: MS
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Kai-Chien
authors.initials: KC
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Chang
authors.affiliation: Genome and Systems Biology Degree Program, National Taiwan University, Academia Sinica, Taiwan.
authors.forename: Kang-Yu
authors.initials: KY
authors.lastname: Tai
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei 106, Taiwan.
authors.forename: Jin-Tung
authors.initials: JT
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan. Electronic address: chingchowchen@ntu.edu.tw.
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055106:Genome-Wide Association Study; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases; D006655:Histone Deacetylases
keywords: Colorectal cancer; HMG-CoA reductase; Histone deacetylase; Preclinical model; Statin hydroxamate