Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer

EBioMedicine

Nai-Wei Chen¹  Jim-Min Fang¹  Ching-Chow Chen²  Kai-Chien Yang²  Yi-Hsin Lin²  Ping Luo²  Yu-Chin Lin²  Tzu-Tang Wei²  Yi-Ting Lin²  Wen-Shu Chen²  Jhih-Bin Chen²  Jin-Tung Liang³  Li-Chun Chang⁴  Ming-Shiang Wu⁴  Kang-Yu Tai⁵  Chia-Tung Shun⁶ 

[1] Department of Chemistry, National Taiwan University, Taipei 106, Taiwan;Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, Taiwan;Department of Surgery, National Taiwan University Hospital, Taipei 106, Taiwan;Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, Taiwan;Genome and Systems Biology Degree Program, National Taiwan University, Academia Sinica, Taiwan;Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan;

关键词: Colorectal cancer;    HMG-CoA reductase;    Histone deacetylase;    Statin hydroxamate;    Preclinical model;   

DOI  :  10.1016/j.ebiom.2016.07.019

来源: DOAJ

【 摘 要 】

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 ApcMin/+ 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.

【 授权许可】

Unknown