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

• HMGR is an oncotarget of CRC.
• JMF3086 targeting HMGR and HDACs is effective therapy in different preclinical CRC models.
• JMF3086 down-regulated inflammatory, proliferation, stemness and anti-apoptotic genes but up-regulated tumor suppressor genes.Addition of chemotherapeutic and molecular targeted agents stepwise prolongs the survival of metastatic colorectal cancer (CRC), implying the importance of new drugs discovery. Furthermore, combination therapy is a rational approach to improve the anti-cancer efficacy. Here, we demonstrate HMGR is a target for CRC and design a dual HMGR and HDAC inhibitor JMF3086. It inhibits tumor progression, metastasis and stemness in several preclinical models, conferring a significant benefit above lovastatin plus SAHA. JMF3086 also potentiates the effect of oxaliplatin, an important chemotherapeutic agent of CRC. These results provide a rationale for clinical studies of JMF3086 to advance the survival of metastatic CRC.

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.