Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer
Journal
EBioMedicine
Journal Volume
10
Pages
124
Date Issued
2016-08
Author(s)
Lin, Yi-Ting
Chen, Wen-Shu
Luo, Ping
Lin, Yu-Chin
Lin, Yi-Hsin
Chen, Jhih-Bin
Chen, Nai-Wei
Fang, Jim-Min
Tai, Kang-Yu
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.
Subjects
Colorectal cancer; HMG-CoA reductase; Histone deacetylase; Preclinical model; Statin hydroxamate
SDGs
Other Subjects
histone deacetylase; histone deacetylase inhibitor; hydroxamic acid; hydroxymethylglutaryl coenzyme A reductase; jmf3086; jmf3171; jmf3173; mevinolin; oxaliplatin; unclassified drug; antineoplastic agent; histone deacetylase; histone deacetylase inhibitor; hydroxymethylglutaryl coenzyme A reductase; hydroxymethylglutaryl coenzyme A reductase inhibitor; angiogenesis; animal cell; animal experiment; animal model; apoptosis; Article; chromatin immunoprecipitation; colorectal cancer; down regulation; drug targeting; female; HCT 116 cell line; inflammation; liver metastasis; male; mouse; nonhuman; priority journal; protein microarray; tumor microenvironment; tumor xenograft; animal; cancer stem cell; Colorectal Neoplasms; disease model; drug effects; drug screening; gene expression regulation; genetics; genome-wide association study; human; metabolism; metastasis; molecularly targeted therapy; pathology; preclinical study; transgenic mouse; Animals; Antineoplastic Agents; Colorectal Neoplasms; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Gene Expression Regulation, Neoplastic; Genome-Wide Association Study; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Mice, Transgenic; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplastic Stem Cells; Xenograft Model Antitumor Assays
Publisher
ELSEVIER SCIENCE BV
Type
journal article