<scp>ETS</scp>1 and <scp>SP</scp>1 drive <i><scp>DHX</scp>15</i> expression in acute lymphoblastic leukaemia

Chen, Xianglei; Cai, Yuanhua; Li, Qiao; Pan, Lili; Shi, Shuiling; Liu, Xiaoli; Chen, Yuan; Li, Jinggang; Wang, Jing; Li, Yang; Li, Xiaofan; Wang, Shaoyuan

doi:10.1111/jcmm.13525

Cited by 9 publications

(4 citation statements)

References 47 publications

(78 reference statements)

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“…Our results also showed that ETS-1 site mutation resulted in more activity reduction compared NF-kB, NF-Y, and ElK-1 sites, as ETS-1 site is overlapped with Sp1 proximal site, mutation of ETS-1 might partially affected the Sp1 activity. In previous studies, the cooperation of Sp1 and ETS-1 in gene regulation was observed [29,30]. Therefore, ETS-1 role can be expected in the Sp1-mediated TMBIM6 expression.…”

Section: Discussionmentioning

confidence: 80%

Expression of TMBIM6 in Cancers: The Involvement of Sp1 and PKC

Junjappa

Kim

Park

et al. 2019

Cancers

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Transmembrane Bax Inhibitor Motif-containing 6 (TMBIM6) is upregulated in several cancer types and involved in the metastasis. Specific downregulation of TMBIM6 results in cancer cell death. However, the TMBIM6 gene transcriptional regulation in normal and cancer cells is least studied. Here, we identified the core promoter region (−133/+30 bp) sufficient for promoter activity of TMBIM6 gene. Reporter gene expression with mutations at transcription factor binding sites, EMSA, supershift, and ChIP assays demonstrated that Sp1 is an essential transcription factor for basal promoter activity of TMBIM6. The TMBIM6 mRNA expression was increased with Sp1 levels in a concentration dependent manner. Ablation of Sp1 through siRNA or inhibition with mithramycin-A reduced the TMBIM6 mRNA expression. We also found that the protein kinase-C activation stimulates promoter activity and endogenous TMBIM6 mRNA by 2- to 2.5-fold. Additionally, overexpression of active mutants of PKCι, PKCε, and PKCδ increased TMBIM6 expression by enhancing nuclear translocation of Sp1. Immunohistochemistry analyses confirmed that the expression levels of PKCι, Sp1, and TMBIM6 were correlated with one another in samples from human breast, prostate, and liver cancer patients. Altogether, this study suggests the involvement of Sp1 in basal transcription and PKC in the enhanced expression of TMBIM6 in cancer.

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Section: Discussionmentioning

confidence: 80%

Expression of TMBIM6 in Cancers: The Involvement of Sp1 and PKC

Junjappa

Kim

Park

et al. 2019

Cancers

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“…Abnormal Sp1 expression and activation are considered to promote human cancer initiation and progression, including leukemia. Evidence demonstrates that Sp1 modulates drug resistance of LSCs by regulating survivin expression [12], and that Sp1 drives DHX15 expression in acute lymphoblastic leukemia [13]. Nevertheless, the role of SP1 driving FUT4 transcription in AML LSCs has not been clarified yet.…”

Section: Introductionmentioning

confidence: 99%

MiR-29b/Sp1/FUT4 axis modulates the malignancy of leukemia stem cells by regulating fucosylation via Wnt/β-catenin pathway in acute myeloid leukemia

Liu

et al. 2019

J Exp Clin Cancer Res

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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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1179-y) contains supplementary material, which is available to authorized users.

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“…DHX15 has been shown to function in multiple biological processes, including pre-mRNA splicing ( Yoshimoto et al., 2009 ), ribosome assembly, and biogenesis ( Chen et al, 2014 ; Memet et al, 2017 ; Studer et al, 2020 ). A few studies suggest that DHX15 contributes to carcinogenesis in leukemia ( Chen et al, 2018 ), breast cancer ( Lin et al, 2009 ), prostate cancer ( Jing et al, 2018 ), and hepatocellular carcinoma ( Xie et al, 2019 ) and acts as a tumor suppressor gene in glioma ( Ito et al, 2017 ) and gastric cancer ( Xiao et al, 2016 ). Importantly, we and other groups have shown that DHX15 is an RNA virus sensor through binding double-stranded RNA (dsRNA) from RNA virus and induces the production of IFN-I and proinflammatory cytokines in dendritic cells (DCs) in response to dsRNA and RNA viruses in vitro ( Lu et al, 2014 ; Mosallanejad et al, 2014 ; Pattabhi et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%