Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer
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...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-08-01
|
| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396416303243 |
| _version_ | 1819238793293594624 |
|---|---|
| author | Tzu-Tang Wei Yi-Ting Lin Wen-Shu Chen Ping Luo Yu-Chin Lin Chia-Tung Shun Yi-Hsin Lin Jhih-Bin Chen Nai-Wei Chen Jim-Min Fang Ming-Shiang Wu Kai-Chien Yang Li-Chun Chang Kang-Yu Tai Jin-Tung Liang Ching-Chow Chen |
| author_facet | Tzu-Tang Wei Yi-Ting Lin Wen-Shu Chen Ping Luo Yu-Chin Lin Chia-Tung Shun Yi-Hsin Lin Jhih-Bin Chen Nai-Wei Chen Jim-Min Fang Ming-Shiang Wu Kai-Chien Yang Li-Chun Chang Kang-Yu Tai Jin-Tung Liang Ching-Chow Chen |
| author_sort | Tzu-Tang Wei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T13:41:52Z |
| format | Article |
| id | doaj.art-ba42b68fffed422db2b013cfbe33aab3 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-23T13:41:52Z |
| publishDate | 2016-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-ba42b68fffed422db2b013cfbe33aab32022-12-21T17:44:50ZengElsevierEBioMedicine2352-39642016-08-0110C12413610.1016/j.ebiom.2016.07.019Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal CancerTzu-Tang Wei0Yi-Ting Lin1Wen-Shu Chen2Ping Luo3Yu-Chin Lin4Chia-Tung Shun5Yi-Hsin Lin6Jhih-Bin Chen7Nai-Wei Chen8Jim-Min Fang9Ming-Shiang Wu10Kai-Chien Yang11Li-Chun Chang12Kang-Yu Tai13Jin-Tung Liang14Ching-Chow Chen15Department of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanGraduate Institute of Forensic Medicine, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDepartment of Chemistry, National Taiwan University, Taipei 106, TaiwanDepartment of Chemistry, National Taiwan University, Taipei 106, TaiwanDivision of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanDivision of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei 106, TaiwanGenome and Systems Biology Degree Program, National Taiwan University, Academia Sinica, TaiwanDepartment of Surgery, National Taiwan University Hospital, Taipei 106, TaiwanDepartment of Pharmacology, National Taiwan University College of Medicine, Taipei 100, TaiwanStatins 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.http://www.sciencedirect.com/science/article/pii/S2352396416303243Colorectal cancerHMG-CoA reductaseHistone deacetylaseStatin hydroxamatePreclinical model |
| spellingShingle | Tzu-Tang Wei Yi-Ting Lin Wen-Shu Chen Ping Luo Yu-Chin Lin Chia-Tung Shun Yi-Hsin Lin Jhih-Bin Chen Nai-Wei Chen Jim-Min Fang Ming-Shiang Wu Kai-Chien Yang Li-Chun Chang Kang-Yu Tai Jin-Tung Liang Ching-Chow Chen Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer EBioMedicine Colorectal cancer HMG-CoA reductase Histone deacetylase Statin hydroxamate Preclinical model |
| title | Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer |
| title_full | Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer |
| title_fullStr | Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer |
| title_full_unstemmed | Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer |
| title_short | Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer |
| title_sort | dual targeting of 3 hydroxy 3 methylglutaryl coenzyme a reductase and histone deacetylase as a therapy for colorectal cancer |
| topic | Colorectal cancer HMG-CoA reductase Histone deacetylase Statin hydroxamate Preclinical model |
| url | http://www.sciencedirect.com/science/article/pii/S2352396416303243 |
| work_keys_str_mv | AT tzutangwei dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT yitinglin dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT wenshuchen dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT pingluo dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT yuchinlin dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT chiatungshun dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT yihsinlin dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT jhihbinchen dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT naiweichen dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT jimminfang dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT mingshiangwu dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT kaichienyang dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT lichunchang dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT kangyutai dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT jintungliang dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer AT chingchowchen dualtargetingof3hydroxy3methylglutarylcoenzymeareductaseandhistonedeacetylaseasatherapyforcolorectalcancer |