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

AbstractStatins 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

The Ninth Visual Object Tracking VOT2021 Challenge Results

acceptedVersionPeer reviewe

Design concepts of desilting tunnel at Shimen Reservoir in Taiwan

[2nd International Workshop on Sediment Bypass Tunnels = 第2回排砂バイパストンネルに関する国際ワークショップ] May 9-12, Kyoto-Japan, 2017.特定研究集会: 29C-01In northern Taiwan, Shimen Reservoir is the main water conservation facility, which has the function of irrigation, electric power generation, water supply, flood prevention and tourism (Figure 1). Through 53 years of operation, the most challenging issue of the reservoir is severe siltation. The capacity of the water conservation is decreasing and 20% of the effective storage volume was lost due to siltation. Furthermore, the frequency of heavy rainfall has increased due to global climate change, so it has become imperative to develop measures to enhance silt-sluicing and flood-discharging capabilities of the reservoir. Accordingly, Water Resources Agency (WRA) planned to build a desilting tunnel, whose intake structure is situated at Amuping area, 7 km upstream from the dam. After completion, the tunnel could carry silt as well as coarse and fine sand outward to the outlet structure. The desilting tunnel is expected to deal with 6.4 × 105 m3 silt per year and increase 600 m3/s flood-discharging capability as well

The design of a crystal-off oscillator with robust on-chip PVT compensation

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Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3‑Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment

A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC₅₀ values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells

The HLTF-PARP1 interaction in the progression and stability of damaged replication forks caused by methyl methanesulfonate

Human HLTF participates in the lesion-bypass mechanism through the fork reversal structure, known as template switching of post-replication repair. However, the mechanism by which HLTF promotes the replication progression and fork stability of damaged forks remains unclear. Here, we identify a novel protein–protein interaction between HLTF and PARP1. The depletion of HLTF and PARP1 increases chromosome breaks, further reduces the length of replication tracks, and concomitantly increases the number of stalled forks after methyl methanesulfonate treatment according to a DNA fiber analysis. The progression of replication also depends on BARD1 in the presence of MMS treatment. By combining 5-ethynyl-2′-deoxyuridine with a proximity ligation assay, we revealed that the HLTF, PARP1, and BRCA1/BARD1/RAD51 proteins were initially recruited to damaged forks. However, prolonged stalling of damaged forks results in fork collapse. HLTF and PCNA dissociate from the collapsed forks, with increased accumulation of PARP1 and BRCA1/BARD1/RAD51 at the collapsed forks. Our results reveal that HLTF together with PARP1 and BARD1 participates in the stabilization of damaged forks, and the PARP1–BARD1 interaction is further involved in the repair of collapse forks

The HLTF–PARP1 interaction in the progression and stability of damaged replication forks caused by methyl methanesulfonate

Human HLTF participates in the lesion-bypass mechanism through the fork reversal structure, known as template switching of post-replication repair. However, the mechanism by which HLTF promotes the replication progression and fork stability of damaged forks remains unclear. Here, we identify a novel protein–protein interaction between HLTF and PARP1. The depletion of HLTF and PARP1 increases chromosome breaks, further reduces the length of replication tracks, and concomitantly increases the number of stalled forks after methyl methanesulfonate treatment according to a DNA fiber analysis. The progression of replication also depends on BARD1 in the presence of MMS treatment. By combining 5-ethynyl-2′-deoxyuridine with a proximity ligation assay, we revealed that the HLTF, PARP1, and BRCA1/BARD1/RAD51 proteins were initially recruited to damaged forks. However, prolonged stalling of damaged forks results in fork collapse. HLTF and PCNA dissociate from the collapsed forks, with increased accumulation of PARP1 and BRCA1/BARD1/RAD51 at the collapsed forks. Our results reveal that HLTF together with PARP1 and BARD1 participates in the stabilization of damaged forks, and the PARP1–BARD1 interaction is further involved in the repair of collapse forks.11Nsciescopu