Dataset Information

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

ABSTRACT: STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-?B, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of IRF7, IRF9, STAT1, and STAT2 Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.

SUBMITTER: Lu L

PROVIDER: S-EPMC5776985 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

Lu Li L Zhu Fen F Zhang Meili M Li Yangguang Y Drennan Amanda C AC Kimpara Shuichi S Rumball Ian I Selzer Christopher C Cameron Hunter H Kellicut Ashley A Kelm Amanda A Wang Fangyu F Waldmann Thomas A TA Rui Lixin L

Proceedings of the National Academy of Sciences of the United States of America 20180102 3

STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analys ...[more]

PMID: 29295936

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Project description:Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.

Dataset Information

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

Publications

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

Similar Datasets

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