Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 13, Pages 9408-9417Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.419861
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Funding
- Yale Center for Molecular Discovery
- Alexander and Margaret Stewart Trust Fellowship
- Breast Cancer Alliance Young Investigator Grant
- Melanoma Research Foundation Career Development Award
- Developmental Research Award from Yale Specialized Programs of Research Excellence (YSPORE) in Skin Cancer
- National Institutes of Health [CA16359, R01 DA025755]
- CTSA Grant from the National Center for Advancing Translational Sciences [UL1 RR024139]
- Clinical and Translational Science Award (CTSA) Scholar Award from Yale Center for Clinical Investigation
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JARID1B (also known as KDM5B or PLU1) is a member of the JARID1 family of histone lysine demethylases responsible for the demethylation of trimethylated lysine 27 in histone H3 (H3K4me3), a mark for actively transcribed genes. JARID1B is overexpressed in several cancers, including breast cancer, prostate cancer, and lung cancer. In addition, JARID1B is required for mammary tumor formation in syngeneic or xenograft mouse models. JARID1B-expressing melanoma cells are associated with increased self-renewal character. Therefore, JARID1B represents an attractive target for cancer therapy. Here we characterized JARID1B using a homogeneous luminescence-based demethylase assay. We then conducted a high throughput screen of over 15,000 small molecules to identify inhibitors of JARID1B. From this screen, we identified several known JmjC histone demethylase inhibitors, including 2,4-pyridinedicarboxylic acid and catechols. More importantly, we identified several novel inhibitors, including 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), which inhibits JARID1B with an IC50 of about 3 mu M in vitro. Consistent with this, PBIT treatment inhibited removal of H3K4me3 by JARID1B in cells. Furthermore, this compound inhibited proliferation of cells expressing higher levels of JARID1B. These results suggest that this novel small molecule inhibitor is a lead compound that can be further optimized for cancer therapy.
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