title: Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells.
abstract: The PRC2 complex protein EZH2 is a histone methyltransferase that is known to bind and recruit DNMT1 to the DNA to modulate DNA methylation. Here, we determined that the pan-HDAC inhibitor panobinostat (LBH589) treatment depletes DNMT1 and EZH2 protein levels, disrupts the interaction of DNMT1 with EZH2, as well as de-represses JunB in human acute leukemia cells. Similar to treatment with the hsp90 inhibitor 17-DMAG, treatment with panobinostat also inhibited the chaperone association of heat shock protein 90 with DNMT1 and EZH2, which promoted the proteasomal degradation of DNMT1 and EZH2. Unlike treatment with the DNA methyltransferase inhibitor decitabine, which demethylates JunB promoter DNA, panobinostat treatment mediated chromatin alterations in the JunB promoter. Combined treatment with panobinostat and decitabine caused greater attenuation of DNMT1 and EZH2 levels than either agent alone, which was accompanied by more JunB de-repression and loss of clonogenic survival of K562 cells. Co-treatment with panobinostat and decitabine also caused more loss of viability of primary AML but not normal CD34(+) bone marrow progenitor cells. Collectively, these findings indicate that co-treatment with panobinostat and decitabine targets multiple epigenetic mechanisms to de-repress JunB and exerts antileukemia activity against human acute myeloid leukemia cells.
authors.affiliation: MCG Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Kate
authors.initials: K
authors.lastname: Buckley
authors.forename: Rekha
authors.initials: R
authors.lastname: Rao
authors.forename: Aditya
authors.initials: A
authors.lastname: Mandawat
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Yang
authors.forename: Rajeshree
authors.initials: R
authors.lastname: Joshi
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Wang
authors.forename: Ramesh
authors.initials: R
authors.lastname: Balusu
authors.forename: Jianguang
authors.initials: J
authors.lastname: Chen
authors.forename: Sanjay
authors.initials: S
authors.lastname: Koul
authors.forename: Atul
authors.initials: A
authors.lastname: Joshi
authors.forename: Sunil
authors.initials: S
authors.lastname: Upadhyay
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Kapil N
authors.initials: KN
authors.lastname: Bhalla
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000077209:Decitabine; D004338:Drug Combinations; D000071221:Enhancer of Zeste Homolog 2 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D000077767:Panobinostat; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D012097:Repressor Proteins; D014157:Transcription Factors; D000077209:Decitabine; D000077767:Panobinostat; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D001374:Azacitidine