Parthenolide specifically depletes histone deacetylase 1 protein and induces cell death through ataxia telangiectasia mutated.
Histone deacetylases (HDACs), enzymes involved in chromatin remodeling, are promising targets for anticancer drug development. Several HDAC inhibitors (HDACi) are in clinical trials. One limitation of present HDACi is their nonspecificity, affecting many HDACs with similar effectiveness. We have identified a small molecule, the sesquiterpene lactone parthenolide (PN), which specifically depletes HDAC1 protein without affecting other class I/II HDACs. HDAC1 depletion occurred through proteasomal degradation and resulted in transcriptional consequences comparable to those observed with pan-HDACi. Surprisingly, HDAC1 depletion did not occur through the inflammation mediator IKK2, a known PN target and regulator of HDAC1. Rather, PN promoted HDAC1 depletion and cell death through the DNA-damage-transducer ataxia telangiectasia mutated. Our study suggests that modulating cellular HDAC protein levels with small molecules provides an alternative approach to specific HDAC inhibition and effective cancer treatment.
Gopal
Y N Vashisht
YN
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Arora
Tarandeep S
TS
Van Dyke
Michael W
MW
D000107:Acetylation; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D006657:Histones; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C493956:CDKN1A protein, human; C002669:parthenolide; C576324:ATM protein, human