Biochem/physiol Actions

Primary TargetJMJD2C/KDM4C

Reversible: yes

Cell permeable: yes

General description

A cell-permeable compound with a Fe(II)-chelating 8-hydroxyquinoline (8HQ) moiety is reported to inhibit KDM4C (IC₅₀ = 30 µM against calf thymus histone H3K9me2 demethylation; [FeSO₄] = 50 µM & [α-ketoglutarate] = 1 mM) and possibly other JMJD2/KDM4 members of Jumonji domain-containing histone demethylases (JHDM). Effectively suppresses androgen receptor (AR) target genes expression in human prostate adenocarcinoma LNCaP cultures upon 100 nM DHT stimulation as well as in CWR22Rv1 cells with constitutively active AR (10 µM) without affecting topoisomerase activity of E. coli Topo I or human Topo II. Shown to prevent AR/genotoxic stress-induced TMPRSS2 chromosomal translocation and gene fusions in LNCaP cells (1/100 & 1/13 of control TMPRSS2ETV1 and TMPRSS2ERG induction level, respectively; 10 µM SD70 dosed 2 h prior to 24 h 50 Gy irradiation & 100 nM DHT) and exhibit anti-proliferation activity against CWR22Rv1 both in cultures (97% decreased vs. 260% increased viable cell number on d6 by MTS assay with or without 10 µM SD70 ) in vitro and in mice (84% growth retardation on d10; 10 mg/4 mL/kg/d i.p.) in vivo without apparent animal toxicity. LNCaP genomic binding sites analyses utilizing Chem-seq with Biotin-derivatized SD70 as well as antibody-based ChIP reveal that 46% of genes upregulated by >1.5-fold upon DHT stimulation have both AR enhancer and SD70-binding sites within 500 kb of the coding gene promoter and 42% of all SD70-suppressed genes in DHT-treated LNCaP cells are DHT-induced genes. Likewise, increased KDM4C binding upon DHT treatment is observed on AR enhancers coocuppied by SD70.

A cell-permeable, bioavailable, non-toxic 8-hydroxyquinolinyl based compound that binds to and colocalizes with androgen receptor (AR) at both ligand-dependent and independent transcriptional regulatory elements. Acts as an inhibitor of dihydotestosterone-regulated gene expression. Shown to inhibit prostate cancer cell transcription by blocking the activity of histone lysine demethylase KDM4C (IC₅₀ = 30 µM). Increases total H3K9me2 levels in 293 T cells in enhancer and promoter regions and causes a slight diminution in the levels of methylated H3K36. Does not affect the activity of DNA/RNA polymerase or topoisomerase I and II activities in any significant manner. Blocks the proliferation of hormone-independent CWR22Rv1 cells in culture (~ 5 µM) and also inhibits their growth in a prostate cancer xenograft murine model (10 mg/kg, i.p.daily).Please note that the molecular weight for this compound is batch-specific due to variable water content.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Jin, C., et al. 2014. Proc. Natl. Acad. Sci. USA111, 9235.

Packaging

25 mg in Glass bottle

Packaged under inert gas

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Warning

Toxicity: Standard Handling (A)