Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531293 | PMC |
| http://dx.doi.org/10.1016/j.celrep.2017.04.077 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Substrate selectivity and inhibition of the human lysyl hydroxylase JMJD7.
Protein Sci
October 2024
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark.
Article Synopsis
- JMJD7 is a human enzyme that specifically modifies lysine residues in certain proteins, which is important for their function.
- Research indicates that JMJD7 has a limited range of substrates compared to other similar enzymes, but can efficiently use altered lysines for its reactions.
- The study identifies ways to inhibit JMJD7 by using variants of its substrates, which could aid in developing targeted therapies against diseases related to JMJD7 activity.
Structure-guided optimisation of -hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-α.
Chem Sci
November 2023
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford United Kingdom
The human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-α (FIH) and HIF-α prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans catalysing hydroxylation of the α-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the -hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition.
View Article and Find Full Text PDF5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.
J Med Chem
August 2023
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, U.K.
Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an -methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles.
View Article and Find Full Text PDFKinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5.
RSC Chem Biol
June 2023
Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford 12 Mansfield Road OX1 3TA Oxford UK
Jumonji-C (JmjC) domain-containing protein 5 (JMJD5) is a human 2-oxoglutarate (2OG) and Fe(ii)-dependent oxygenase which catalyses the post-translational C3 hydroxylation of arginyl-residues and which is linked to the circadian rhythm and to cancer biology through as yet unidentified mechanisms. We report robust solid phase extraction coupled to mass spectrometry (SPE-MS)-based JMJD5 assays which enable kinetic and high-throughput inhibition studies. The kinetic studies reveal that some synthetic 2OG derivatives, notably including a 2OG derivative with a cyclic carbon backbone ( (1)-3-(carboxycarbonyl)cyclopentane-1-carboxylic acid), are efficient alternative cosubstrates of JMJD5 and of factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH), but not of the Jumonji-C (JmjC) histone -methyl lysine demethylase KDM4E, apparently reflecting the closer structural similarity of JMJD5 and FIH.
View Article and Find Full Text PDFInhibition of KDM7A/B histone demethylases restores H3K79 methylation and protects against osteoarthritis.
Ann Rheum Dis
July 2023
Development and Regeneration, Skeletal Biology and Engineering Research Center, Laboratory of Tissue Homeostasis and Disease, KU Leuven, Leuven, Belgium
Objectives: In osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!