title: HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML.
abstract: Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77(-/-)nor1(-/-) mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally downregulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275 restored the expression of Nur77/Nor1 and induced expression of activator protein 1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34(+)/38(-) AML LSCs. Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally upregulated by SNDX-275 in AML cells and in LSCs. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of activator protein 1 transcription factors, a death receptor and pro-apoptotic proteins.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: V R
authors.initials: VR
authors.lastname: Ruvolo
authors.forename: T
authors.initials: T
authors.lastname: McQueen
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: I J
authors.initials: IJ
authors.lastname: Samudio
authors.forename: O
authors.initials: O
authors.lastname: Conneely
authors.forename: M
authors.initials: M
authors.lastname: Konopleva
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D017931:DNA Primers; D005434:Flow Cytometry; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D026901:Membrane Transport Proteins / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D026901:Membrane Transport Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C479458:OSCP1 protein, human; D011725:Pyridines; C118739:entinostat