Synergistic Induction of Galectin-1 by CCAAT/Enhancer Binding Protein α and Hypoxia-inducible Factor 1α and Its Role in Differentiation of Acute Myeloid Leukemic Cells

Zhao, Xu; Zhao, Kangfei; Jiang, Yi; Zhao, Meng; Chen, Guo Qiang

doi:10.1074/jbc.m111.247262

Cited by 40 publications

(36 citation statements)

References 43 publications

(43 reference statements)

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“…More interestingly, hypoxia also decreased the expression of miR-17 and miR-20a in both AML cell lines (Supplementary Figures S3B, C S4B and C). Consistent with previous findings, 5,15 hypoxia also triggered growth arrest (Supplementary Figures S3D and S4D) and differentiation, as evidenced by the expression of CD11c, a mature myeloid cell surface marker (Supplementary Figures S3E and S4E). Moreover, when HIF-1a was knocked down in the parental U937 cell line, hypoxia-induced miR-17 and miR-20a downregulation (Supplementary Figures S5A-C) was abrogated, suggesting that HIF-1a suppresses miR-17 and miR-20a expression during hypoxia.…”

Section: Resultssupporting

confidence: 76%

“…This is possibly due to the longer time course compared with the in vitro experiments (the in vivo experiments were conducted 21 days (for proliferation) and 10 days (for differentiation) after transplantation, respectively, while the in vitro experiments were conducted 6 days after tetracycline withdrawal). Moreover, other HIF-1a-regulated factors such as gelactin-1 15 and the bone marrow environment could also have some influence on the transplanted human cells. Collectively, our data indicate that miR-20a inhibits the cellular differentiation and reduced proliferation induced by HIF-1a in leukemic cells in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…9 U937T stable transformants with inducible C/EBPa and empty vector (U937T C/EBPa and U937T PTRE ) were established as described previously. 15 All cell lines were cultured in 5% CO 2 /95% air in a humidified atmosphere at 371C. For hypoxic treatment, the NB4 and U937 transformants were cultured in a specially designed hypoxia incubator (Thermo Electron, Forma, MA, USA) in an atmosphere that consists of 94% N 2 , 5% CO 2 , and 1% O 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The NBT reduction test was performed as previously described. 15 The distribution of nuclear DNA contents was analyzed by flow cytometry (Beckman-Coulter).…”

Section: Methodsmentioning

confidence: 99%

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HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The NBT reduction test was performed as previously described. 15 The distribution of nuclear DNA contents was analyzed by flow cytometry (Beckman-Coulter).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Transcription factors known as hypoxia-inducible factors (HIFs) bind hypoxia responsive elements (HREs) within the promoter regions of their target genes [4,5]. HIF target genes include those involved in the regulation of hematopoietic and vascular development, cellular glucose uptake and metabolism, cell proliferation and differentiation, pH homeostasis, cell death and autophagy [6][7][8][9][10][11][12][13][14].…”

mentioning

confidence: 99%

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Jiao

et al. 2014

Sci. China Life Sci.

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Hypoxia-inducible factor-1 (HIF-1) is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia, a common feature of the microenvironment in solid tumors. The transcriptional activity, protein stabilization, protein-protein interactions and cellular localization of HIF-1, an oxygen-sensitive subunit of HIF-1, are mainly modulated by various post-translational modifications. Recently, we reported that polycomb chromobox 4 (Cbx4) governs the transcriptional activity of HIF-1α by enhancing its sumoylation at K391 and K477, through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma. This review summarizes the current knowledge of HIF-1 sumoylation and its roles in the pathogenesis of cancer.

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Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia

et al. 2022

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Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co‐expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T‐lymphoid/myeloid MPAL (T/My MPAL‐NOS), 42 with Ph+ MPAL, 36 with B‐lymphoid/myeloid MPAL (B/My MPAL‐NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL‐NOS was similar to B/T MPAL‐NOS but differed from Ph+ MPAL and B/My MPAL‐NOS. T/My MPAL‐NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL‐NOS showed higher NOTCH1 mutations. By integrating next‐generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1–G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement‐like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement‐like characteristics. Subsequently, we analyzed single‐cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease‐like and common myeloid progenitor disease‐like signatures, G5 and G6 had high expression of granulocyte‐monocyte progenitor disease‐like and monocyte disease‐like signatures, and G7 and G8 had common lymphoid progenitor disease‐like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.

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Synergistic Induction of Galectin-1 by CCAAT/Enhancer Binding Protein α and Hypoxia-inducible Factor 1α and Its Role in Differentiation of Acute Myeloid Leukemic Cells

Cited by 40 publications

References 43 publications

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia

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