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Mir-29B/Sp1/FUT4 Axis Modulates the Malignancy of Leukemia Stem

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Mir-29B/Sp1/FUT4 Axis Modulates the Malignancy of Leukemia Stem Liu et al. Journal of Experimental & Clinical Cancer Research (2019) 38:200 https://doi.org/10.1186/s13046-019-1179-y RESEARCH Open Access MiR-29b/Sp1/FUT4 axis modulates the malignancy of leukemia stem cells by regulating fucosylation via Wnt/β-catenin pathway in acute myeloid leukemia Bing Liu1†, Hongye Ma2†, Qianqian Liu1, Yang Xiao1, Shimeng Pan1, Huimin Zhou3 and Li Jia1* Abstract Background: Acute myeloid leukemia (AML) is initiated and maintained by a unique, small subset of leukemia stem cells (LSCs). LSCs are characterized by unrestricted self-renewal and contribute to the malignancy of leukemia. Aberrant protein fucosylation is associated with AML progression. However, it is still less understood that the miR-29b/Sp1/FUT4 crosstalk involved in the fucosylation-mediated LSCs malignancy in AML. Methods: AML cell lines were sorted by magnetic microbeads to obtain the CD34 + CD38- sub-population. The key biomarkers for LSCs were identified by flow cytometry. Fucosyltransferase genes were screened by qRT-PCR, and FUT4 was focused. Effect of FUT4 on LSCs malignancy was determined by CCK8 assay, sphere formation assay, immunofluorescence staining, apoptosis and in vivo xenografts experiments. The linkage of FUT4 promoter and Sp1 was confirmed by dual-luciferase reporter gene assay. ChIP-PCR assay was used to show the directly binding of Sp1 and FUT4 promoter. Activity of Wnt//β-catenin pathway was determined by western blot. Overall survival curves were diagrammed by Kaplan-Meier analysis. Results: Here, the expressional profiles of 11 fucosyltransferase genes were different comparing LSCs and non-LSCs of KG-1a and MOLM13 cells, whereas CD34 + CD38- cells exhibited higher expression of FUT4. Functionally, alteration of FUT4 in CD34 + CD38- cells modulated LSCs malignant behaviors both in vitro and in vivo. Transcriptional inhibitor actinomycin D (Act D) or translational inhibitor cycloheximide (CHX) prevented LSCs progression, and Sp1 was identified as the efficient regulator of FUT4 transcription. Moreover, miR-29b directly affected the binding of Sp1 and FUT4 promoter region, which further mediated LSCs proliferation, apoptosis and drug-resistance through fucosylated-CD44 via activation of Wnt/β-catenin pathway. Clinically, Sp1 and FUT4 were up-regulated and positively correlated with poor overall survival of AML patients. Conclusion: These data indicated that miR-29b/Sp1/FUT4 axis promoted the malignant behaviors of LSCs by regulating fucosylated CD44 via Wnt/β-catenin pathway. Identifying LSCs surface markers and targeting LSCs were important for the development of potential therapies in AML. Keywords: AML, LSCs, FUT4, Sp1, miR-29b, Wnt/β-catenin pathway * Correspondence: [email protected] †Bing Liu and Hongye Ma contributed equally to this work. 1College of Laboratory Medicine, Dalian Medical University, 9 Lushunnan Road Xiduan, Dalian 116044, Liaoning Province, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Journal of Experimental & Clinical Cancer Research (2019) 38:200 Page 2 of 14 Background transcription through binding to the 3′-UTR of target Acute myeloid leukemia (AML) is an aggressive malig- mRNA [14]. MiRNAs are also important regulators of nancy of the hematopoietic system, which is character- hematopoiesis, and altered miRNAs expression are ized by the clonal proliferation and differentiation into strongly associated with the pathogenesis of hematologic immature hematopoietic cells of dysfunctional myeloid malignancies [15]. Among the reported miRNAs, the precursors [1]. Despite progress made in the treatment lower expression of miR-34c-5p in LSCs is closely corre- of AML, most patients suffer relapses of the disease [2]. lated with the adverse prognosis and poor responses to AML is typically a stem cell-driven disease, and the ex- therapy of AML patients [16]. MiR-99 is highly istence of leukemia stem cells (LSCs) is first identified expressed in hematopoietic stem cells (HSCs) and LSCs, (CD34 + CD38-) by JE Dick in 1994 [3]. Accumulating and regulates self-renewal in both HSCs and LSCs of evidence shows that LSCs drive the initiation and per- AML [17]. Although several miRNAs have been re- petuation of AML, whereas show less sensitive to ported to regulate LSCs malignancy of AML, the specific chemotherapy. LSCs are major clinical factors in disease role of fucosylation that modulates LSCs malignancy of progression and relapse, and increasingly being used as AML by miR-29b directly targeting Sp1 to drive FUT4 is critical target for clinical therapeutic intervention [4, 5]. not well understood. LSCs also exhibit stem cell-like characteristics such as In the present study, the expression pattern of FUTs in the capacity for self-renewal, multi-potent differentiation LSCs was examined, and the increased level of FUT4 in potential and relative quiescence [6]. Therefore, it is im- LSCs was positively associated with AML malignancy. portant to target these malignant cells and investigate MiR-29b mediated Sp1 expression, which further facili- the intricate mechanisms to improve outcomes of AML tated FUT4 level in LSCs. Furthermore, the underlying patients. mechanism involved in miR-29b/Sp1/FUT4-regulated Glycosylation is arguably the most abundant and com- malignancy through CD44 fucosylation via Wnt/β-ca- plicated form of post-translational modification found in tenin pathway was explored in LSCs of AML. mammalian cells. Fucosylation is one of the most im- portant types of glycosylation in cancer. Aberrant fuco- Materials and methods sylation of proteins is a well-known hallmark of cancer Cell culture and clinical samples and represents a valuable source of cells interaction [7]. The AML cell lines, KG-1a was obtained from the ATCC All fucosylation reactions in cells are catalyzed by fuco- cell bank, while MOLM13 was purchased from the Ger- syltransferases (FUTs). So far, 13 different FUTs have man Collection of Microorganisms and Cell Culture been identified in the human genome, including FUT1 (DSMZ, Braunschweig, Germany). Cells were cultured in to 11, protein O-fucosyltransferase 1 (POFUT1), and RPMI 1640 medium (Gibco) supplemented with 10% fetal POFUT2 [8]. FUT4 cDNA isolated from the HL-60 cell bovine serum (Gibco) and 1% penicillin-streptomycin corresponds to myeloid type fucosyltransferase [9]. (Gibco) at 37 °C in air containing 5% CO2. Cells were sep- FUT4 mRNA was also highly expressed in both colon arated and enriched for CD34 + CD38- cells using mag- adenocarcinoma and myeloid cell lines [9, 10]. However, netic microbeads (MiltenyiBiotec, Auburn, CA, USA) and the exact molecular function of FUT4 during AML pro- labeled with CD34-FITC, CD38-PE, or isotype control gression and whether FUT4 could be a potential thera- antibodies. peutic target remains largely unknown. Peripheral blood mononuclear cells (PBMCs) were Specificity protein 1 (Sp1) is a sequence-specific collected from 50 newly diagnosed AML patients com- DNA-binding protein, which is involved in the activation prising 28 males and 22 females with age ranging from and regulation of cellular transcription. Thus, Sp1 is an 18 to 65 years (median age of 38.8 years). The samples essential transcription factor for many genes [11]. Ab- were obtained from the First Affiliated Hospital of Da- normal Sp1 expression and activation are considered to lian Medical University (Dalian, China) from Jan 2016 to promote human cancer initiation and progression, in- Feb 2018. Our work was approved by the Institutional cluding leukemia. Evidence demonstrates that Sp1 mod- Ethics Committee of the First Affiliated Hospital of ulates drug resistance of LSCs by regulating survivin Dalian Medical University (Ethics Reference NO: expression [12], and that Sp1 drives DHX15 expression YJ-KY-FB-2016-45). PBMCs of AML were obtained by in acute lymphoblastic leukemia [13]. Nevertheless, the Ficoll-Hypaque density gradient centrifugation (Sig- role of SP1 driving FUT4 transcription in AML LSCs ma-Aldrich) and were further cultured in plastic dishes has not been clarified yet. to remove adherent cells at 37 °C for 24 h. PBMCs cells In recent years, a number of studies on prognostic were purified for CD34 + CD38- cells using magnetic markers in AML have focused on microRNAs (miR- microbeads. The purity of enriched CD34 + CD38- was NAs), which lack protein-coding potential. MiRNAs are evaluated by staining with FITC-conjugated anti-CD34 approximately 22 nucleotides in length, which inhibit and CD38-PE. By adding B27 (1:50; Life Technologies, Liu et al. Journal of Experimental & Clinical Cancer Research (2019) 38:200 Page 3 of 14 Carlsbad, CA, USA), 10 ng/mL basic fibroblast growth Methylcellulose colony formation assay factor (bFGF) and 20 ng/mL epidermal growth factor The colony-forming capacity of LSCs (CD34 + CD38-) of (EGF), the CD34 + CD38- cells were maintained in KG-1a and MOLM13 cells were measured using methyl- DMEM/F12K medium.
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