title: Caspase-3 and caspase-6 cleave STAT1 in leukemic cells.
abstract: Signal Transducer and Activator of Transcription-1 (STAT1) is phosphorylated upon interferon (IFN) stimulation, which can restrict cell proliferation and survival. Nevertheless, in some cancers STAT1 can act in an anti-apoptotic manner. Moreover, certain malignancies are characterized by the overexpression and constitutive activation of STAT1. Here, we demonstrate that the treatment of transformed hematopoietic cells with epigenetic drugs belonging to the class of histone deacetylase inhibitors (HDACi) leads to the cleavage of STAT1 at multiple sites by caspase-3 and caspase-6. This process does not occur in solid tumor cells, normal hematopoietic cells, and leukemic cells that underwent granulocytic or monocytic differentiation. STAT1 cleavage was studied under cell free conditions with purified STAT1 and a set of candidate caspases as well as with mass spectrometry. These assays indicate that unmodified STAT1 is cleaved at multiple sites by caspase-3 and caspase-6. Our study shows that STAT1 is targeted by caspases in malignant undifferentiated hematopoietic cells. This observation may provide an explanation for the selective toxicity of HDACi against rapidly proliferating leukemic cells.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany. Friedrich-Schiller-Universität Jena, Centre for Molecular Biomedicine (CMB), Institute for Biochemistry and Biophysics, Hans-Knöll-Str. 2, 07745 Jena, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Licht
authors.forename: Katrin
authors.initials: K
authors.lastname: Noack
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schlott
authors.forename: Martin
authors.initials: M
authors.lastname: Förster
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schlenker
authors.forename: Andreas
authors.initials: A
authors.lastname: Licht
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Krämer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Heinzel
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D053178:Caspase 6 / Q000378:metabolism*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053148:Caspase 3; D053178:Caspase 6