Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Liu, Shujun; Wu, Lai-Chu; Pang, Jiuxia; Santhanam, Ramasamy; Schwind, Sebastian; Wu, Yue; Hickey, Christopher; Yu, Jianhua; Becker, Heiko; Maharry, Kati; Radmacher, Michael D.; Li, Chenglong; Whitman, Susan P.; Mishra, Anjali; Stauffer, Nicole; Eiring, Anna M.; Briesewitz, Roger; Baiocchi, Robert A.; Chan, Kenneth K.; Paschka, Peter; Caligiuri, Michael A.; Byrd, John C.; Croce, Carlo M.; Bloomfield, Clara D.; Perrotti, Danilo; Garzon, Ramiro; Marcucci, Guido

doi:10.1016/j.ccr.2010.03.008

Cited by 233 publications

(290 citation statements)

References 39 publications

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“…31 Mithramycin A exposure led to a decrease in mRNA levels only on those target genes with Sp1 and non-AML1 TFBS at their promoters (that is, CTCF and SIRT1) but showed no effect on those genes with Sp1 and AML1 TFBS (that is, AML1 and YES1; Figure 5), supporting our hypothesis of Sp1 driving AML1-ETO binding to genes where Sp1 but not AML1 TFBS is present.…”

supporting

confidence: 67%

“…This fact further supports previous data indicating that AML1-ETO and Sp1 are recruited to promoters as a complex. 31 Furthermore, our study indicates that this DNA binding mechanism occurs in a genome-wide manner.…”

mentioning

confidence: 99%

“…30 For mithramycin A experiments, KIT (a known Sp1 target) expression was used as positive control. 31 …”

Section: Quantitative Real-time Rt-pcrmentioning

confidence: 99%

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Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

et al. 2012

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The AML1-ETO fusion protein, which is present in 10 --15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.Leukemia ( Keywords: AML1-ETO; myeloid leukemia ; histone deacetylation; H3K9me3; Sp1 INTRODUCTIONThe presence of the AML1-ETO fusion protein indicates acute myeloid leukemia (AML) with t(8;21)(q22;q22), which accounts for B10 --15% of all AML cases.1,2 This product is the consequence of a reciprocal translocation that fuses the DNA binding domain of the AML1 transcription factor essential for transcriptional activation of genes involved in normal hematopoiesis in frame with nearly the entire ETO protein, a transcriptional repressor molecule expressed in a variety of tissues.

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supporting

confidence: 67%

mentioning

confidence: 99%

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Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

et al. 2012

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“…In AML, miR-29B downregulation has been found to be associated with high C-MYC levels as well as high SP1 and NF-κB. 33,34 Furthermore, NF-κB, JUN and C-MYC have been linked to increased NRF2 activity in human cancer (including AML) 10,35 and NRF2 has been shown to transcriptionally regulate miR-125B in kidney epithelia cells in response to cisplatin-induced toxicity. 36 Taken together, it is likely that NRF2 has a central role in the complex network regulating miR-29B and miR-125B in human AML.…”

Section: Discussionmentioning

confidence: 99%

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

et al. 2014

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Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics.

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“…6,27 Both NO and HDACs are able to modulate microRNA expression. 14,28 To investigate the additive contribution of the hybrid 2 compared to those made by its single components, we ran microRNA profiling, with TaqMan Human MicroRNA-B Arrays version 2.0 (Applied Biosystems, Foster City, CA). HaCaT cells were treated with 2 (10 μM) for 1 h. At the end of treatment, cells were collected and lysed with Trizol for total RNA extraction.…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor

Borretto

Lazzarato

Spallotta

et al. 2013

ACS Med. Chem. Lett.

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The NO-donor histone deacetylase inhibitor 2, formally obtained by joining Entinostat 1, a moderately selective Class I histone deacetylases (HDACs) inhibitor, to a 4-(methylaminomethyl)furoxan-3-carbonitrile scaffold, is described and its preliminary biological profile discussed. This hybrid regulates Classes I and II HDACs. Nitric oxide (NO) released by the compound activates soluble guanylate cyclase (sGC), causing Class II nuclear shuttling and chromatin modifications, with consequences on gene expression. The hybrid affects a number of micro-RNAs not modulated by its individual components; it promotes myogenic differentiation, inducing the formation of larger myotubes with significantly more nuclei per fiber, in a more efficient manner than the 1:1 mixture of its two components. The hybrid is an example of a new class of NO-donor HDACs now being developed, which should be of interest for treating a number of diseases. KEYWORDS: HDAC, histone deacetylase inhibitors, NO-donor, multitarget drugs, epigenetics H istone deacetylases (HDACs) are a family of epigenetic enzymes that catalyze the hydrolysis of acetylated ε-amino groups of Lys in H3 and H4 histone tails. 1 Removal of the acetyl groups restores the positive charge of Lys residues, enabling them to interact with the negative phosphate groups of DNA, with consequent chromatin tightness and transcriptional repression. 2 The converse occurs under the action of another family of enzymes, the histone acetyltransferases (HATs), which catalyze the transfer of acetyl groups from acetyl-CoA to lysine residues in H3 and H4 histone tails inducing DNA unwinding and chromatin decondensation, with potential transcriptional activation.Human HDACs are a family of 18 enzymes grouped into four classes (I, II, III, and IV). 3 Class III HDACs, also known as "sirtuins", are NAD-dependent deacetylase enzymes, whereas Classes I, II, and IV are zinc-dependent metalloproteins. Class I HDACs comprise HDAC1, 2, 3, and 8, which have conserved structure and similar functions, but rather different distributions: HDAC1 and 2 are mostly nuclear, while HDAC3 and HDAC8 are tissue-specific and present either in the nuclear or in the cytoplasmatic compartments. 1,3−5 Class II HDACs are more structurally complex, and their functions are not yet clear. Class II is further divided into subclasses IIa (HDAC4, 5, 7, and 9) and IIb (HDAC6 and 10). The members of Class II are localized in the cytosol when they are phosphorylated, whereas their dephosphorylation enables them to translocate into the nucleus (nuclear shuttling) with consequent histone deacetylation and gene repression. 6 HDAC11, a poorly characterized enzyme, is the sole member of class IV and is primarily nuclear. Lastly, the members of Class III (the sirtuins) show no homology with the other classes and preferentially deacetylate nonhistone substrates. 7 Nitric oxide (NO) is a well-known gaseous molecule that plays very important roles in mammalian physiology and pathophysiology. In the cardiovascular system, NO contrib...

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Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia

Cited by 233 publications

References 39 publications

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor

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