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

L. Zhou, V. R. Ruvolo, T. McQueen, W. Chen, I. J. Samudio, O. Conneely, M. Konopleva, M. Andreeff

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1358-1368
Number of pages11
JournalLeukemia
Volume27
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

Apoptosis Regulatory Proteins
Histone Deacetylases
Acute Myeloid Leukemia
Leukemia
Transcription Factors
Myeloid Cells
Death Domain Receptors
Histone Deacetylase Inhibitors
Stem Cells
Transcription Factor AP-1
Noxae
Orphan Nuclear Receptors
Apoptosis
Cytoplasmic and Nuclear Receptors
entinostat
Down-Regulation

Keywords

  • AML
  • apoptosis
  • Nur77/Nor1
  • SNDX-275

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

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. / Zhou, L.; Ruvolo, V. R.; McQueen, T.; Chen, W.; Samudio, I. J.; Conneely, O.; Konopleva, M.; Andreeff, M.

In: Leukemia, Vol. 27, No. 6, 06.2013, p. 1358-1368.

Research output: Contribution to journalArticle

Zhou, L. ; Ruvolo, V. R. ; McQueen, T. ; Chen, W. ; Samudio, I. J. ; Conneely, O. ; Konopleva, M. ; Andreeff, M. / 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. In: Leukemia. 2013 ; Vol. 27, No. 6. pp. 1358-1368.
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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.",
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