C/EBPα and PU.1 are involved in distinct differentiation responses of acute promyelocytic leukemia HL-60 and NB4 cells via chromatin remodeling

Savickienė, Jūratė; Treigytė, Gražina; Vistartaite, Giedre; Tunaitis, Virginijus; Magnusson, Karl‐Eric; Navakauskienė, Rūta

doi:10.1016/j.diff.2010.08.003

Cited by 13 publications

(9 citation statements)

References 49 publications

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“…5a). Importantly, the delayed differentiation effect in NB4 cells by belinostat is consistent with our previous reports, using different HDAC inhibitors, such as sodium butyrate, FK228, and BML-210 [39][40][41]. Moreover, this occurs in association with the downregulation of cyclin E1 and upregulation of p27 [38].…”

Section: Discussionsupporting

confidence: 91%

Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

et al. 2014

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Therapeutic strategies targeting histone deacetylase (HDAC) inhibition have become promising in many human malignancies. Belinostat (PXD101) is a hydroxamate-type HDAC inhibitor tested in phase I and II clinical trials in solid tumors and hematological cancers. However, little is known about the use of belinostat for differentiation therapy against acute myelogenous leukemia. Here, we characterize the antileukemia activity of belinostat as a single drug and in combination with all-trans-retinoic acid (RA) in promyelocytic leukemia HL-60 and NB4 cells. Belinostat exerted dose-dependent growth-inhibitory or proapoptotic effects, promoting cell cycle arrest at the G0/G1 or the S transition. Apoptosis was accompanied by activation of caspase 3, degradation of PARP-1, and cell cycle-dependent changes in the expression of survivin, cyclin E1, and cyclin A2. Belinostat induced a dose-dependent reduction in the expression of EZH2 and SUZ12, HDAC-1, HDAC-2, and histone acetyltransferase PCAF (p300/CBP-associated factor). Belinostat increased acetylation of histone H4, H3 at K9 and H3 at K16 residues in a dose-dependent manner, but did not reduce trimethylation of H3 at K27 at proapoptotic doses. Combined treatment with belinostat and RA dose dependently accelerated and reinforced granulocytic differentiation, accompanied by changes in the expression of CD11b, C/EBPα (CCAAT/enhancer binding protein-α), and C/EBPε. Our results concluded the usefulness of belinostat, as an epigenetic drug, for antileukemia and differentiation therapy.

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Section: Discussionsupporting

confidence: 91%

Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

et al. 2014

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“…We believe that this may instead result from the ability of PU.1 or C/EBPα to induce different sets of genes, besides a common set of genes, during osteoclastogenesis. Our notion is underscored by a recent study demonstrating that C/EBPα and PU.1 exhibit distinct responses in the human acute leukemia HL-60 and NB4 cell lines (55). …”

Section: Discussionmentioning

confidence: 80%

C/EBPα and PU.1 exhibit different responses to RANK signaling for osteoclastogenesis

Jules

Chen

2018

Bone

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The transcription factors C/EBPα and PU.1 are upregulated by RANKL through activation of its receptor RANK during osteoclastogenesis and are critical for osteoclast differentiation. Herein we investigated the mechanisms underlying how C/EBPα and PU.1 regulate osteoclast differentiation in response to RANK signaling. We showed that C/EBPα or PU.1 overexpression could initiate osteoclastogenesis and upregulate the expressions of the osteoclast genes encoding the nuclear factor of activated T-cells, C1, cathepsin K, and tartrate-resistant acid phosphatase independently of RANKL. However, while PU.1 upregulated C/EBPα, C/EBPα could not upregulate PU.1. RANK has a unique cytoplasmic domain, 535IVVY538 motif, which is crucial for osteoclast differentiation. We demonstrated that mutational inactivation of RANK IVVY motif blocked osteoclast differentiation and significantly attenuated C/EBPα, but not PU.1, expression, indicating that RANK-IVVY-induced signaling is dispensable to PU.1 upregulation during osteoclastogenesis. However, C/EBPα or PU.1 overexpression failed to promote osteoclastogenesis in cells expressing mutated RANK IVVY motif. We noted that RANK-IVVY-motif inactivation significantly repressed osteoclast genes as compared with a vector control, suggesting that IVVY motif might also negatively regulate osteoclast inhibitors during osteoclastogenesis. Consistently, IVVY-motif inactivation triggered upregulation of RBP-J, a potent osteoclast inhibitor, during osteoclastogenesis. Notably, C/EBPα or PU.1 overexpression in cells expressing mutated RANK IVVY motif failed to control the deregulated RBP-J expression, resulting in repression of osteoclast genes. Accordingly, RBP-J silencing in the mutant cells rescued osteoclastogenesis with C/EBPα or PU.1 overexpression. In conclusion, we revealed that while PU.1 and C/EBPα are critical for osteoclastogenesis, they respond differently to RANKL-induced activation of RANK IVVY motif.

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“…However, in the other promyelocytic cell line NB4, SLC11A1 is not prone to transcriptional activation. Epigenetic differences between HL-60 and NB4 cells alter their response to VitD, which induces differentiation by genomic (VDR) or non-genomic mechanisms, respectively, [95,187,193]. Studying SLC11A1 locus can thus help evidence molecular aberrations that occur in myelo-monocytic leukemia.…”

Section: Discussionmentioning

confidence: 99%

“…Differential pharmacological modulation of histone modifications have previously been reported with NB4 and HL-60 cell lines; such as H4 acetylation in the G-CSF receptor promoter at the C/EBPα binding site in HL-60 but not in NB4 cells [187]. Interactions detected in HL-60 cells between SLC11A1 putative 5' enhancer and RNA Pol II, GABP and PU.1 (Figure 3F) indicate the possibility that the relevant elements are active in these cells whereas they are not in NB4 and K-562 cells.…”

Section: Patterns Of Histone Marks and Transcription Factor Bindinmentioning

confidence: 99%

Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes

Cellier

2013

Biology

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The Natural resistance-associated macrophage protein 1 (Nramp1 or Solute carrier 11 member 1, Slc11a1) transports divalent metals across the membrane of late endosomes and lysosomes in professional phagocytes. Nramp1 represents an ancient eukaryotic cell-autonomous defense whereas the gene duplication that yielded Nramp1 and Nramp2 predated the origin of Sarcopterygians (lobe-finned fishes and tetrapods). SLC11A1 genetic polymorphisms associated with human resistance to tuberculosis consist of potential regulatory variants. Herein, current knowledge of the regulation of SLC11A1 gene expression is reviewed and comprehensive analysis of ENCODE data available for hematopoietic cell-types suggests a hypothesis for the regulation of SLC11A1 expression during myeloid development and phagocyte functional polarization. SLC11A1 is part of a 34.6 kb CTCF-insulated locus scattered with predicted regulatory elements: a 3' enhancer, a large 5' enhancer domain and four elements spread around the transcription start site (TSS), including several C/EBP and PU.1 sites. SLC11A1 locus ends appear mobilized by ETS-related factors early during myelopoiesis; activation of both 5' and 3' enhancers in myelo-monocytic cells correlate with transcription factor binding at the TSS. Characterizing the corresponding cis/trans determinants functionally will establish the mechanisms involved and possibly reveal genetic variation that impacts susceptibility to infectious or immune diseases.

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C/EBPα and PU.1 are involved in distinct differentiation responses of acute promyelocytic leukemia HL-60 and NB4 cells via chromatin remodeling

Cited by 13 publications

References 49 publications

Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

Epigenetic and molecular mechanisms underlying the antileukemic activity of the histone deacetylase inhibitor belinostat in human acute promyelocytic leukemia cells

C/EBPα and PU.1 exhibit different responses to RANK signaling for osteoclastogenesis

Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes

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