BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

Camicia, Rosalba; Bachmann, Stephan; Winkler, Hans Christian; Beer, Markus; Tinguely, Marianne; Haralambieva, Eugenia; Hassa, Paul O.

doi:10.1242/jcs.118174

Cited by 52 publications

(109 citation statements)

References 58 publications

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“…Whereas BAL1 has been shown to be overexpressed in diffuse large B cell lymphomas, 41 none of our patients sampled for CD19+ B cells had a previous lymphoma. Disease annotation analysis of the top DMCs in whole blood also pointed to an extensive enrichment of genes associated with lymphoproliferative disorders, including B cell non-Hodgkin's lymphoma.…”

Section: In Pss Cd4+ T Cells and Subsequently Bymentioning

confidence: 64%

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

et al. 2016

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ObjectivesIncreasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.MethodsGenome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.ResultsWe identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.ConclusionsOur study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

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Section: In Pss Cd4+ T Cells and Subsequently Bymentioning

confidence: 64%

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

et al. 2016

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“…Several studies have shown that STAT3 and STAT5 are required for cell growth, proliferation, survival, invasion and metastasis of many PCa subtypes [1,2,5-10]. In addition, STAT1 has been recently identified as a proto-oncogene product in a variety of cancers, including metastatic PCa (mPCa) [11-23]. A recent study has shown that 29% of clinical human mPCa’s analyzed, constitutively expressed STAT1 and IFN-stimulated genes in vivo [12].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously demonstrated that the ADP-ribosyltransferase-9 (ARTD9), also known as B-aggressive lymphoma protein (BAL1) and PARP9, acts as a novel oncogenic survival factor in high-risk, chemo-resistant, host response (HR) sub-types of diffuse large B-Cell lymphoma (HR-DLBCL) and as a crucial negative and positive co-regulator of IFNγ/STAT1-signaling [23]. ARTD9 is an inactive mono-ADP-ribosyltransferase belonging to the intracellular Diphteria toxin-like glutamate/aspartate-specific mono- and polymerizing-ADP-ribosyltransferase (ARTD) family (also known as PARPs) [38] that also includes the active mono-ADP-ribosyltransferase ARTD8 (also known as PARP14) [38-41].…”

Section: Introductionmentioning

confidence: 99%

“…Like ARTD9, ARTD8 contains several evolutionary conserved macrodomains, which have been recently shown to act as binding modules for free and protein-linked mono- or poly-ADP-ribose [42-44]. ARTD9 counteracts the IFNγ-dependent anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis and induces an oncogenic switch in high-risk HR-DLBCL that transforms STAT1 from a tumor suppressor to a proto-oncogene [23]. As a consequence, ARTD9 mediates proliferation, survival and chemo-resistance in HR-DLBCL [23].…”

Section: Introductionmentioning

confidence: 99%

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DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

et al. 2014

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BackgroundProstate cancer (PCa) is one of the leading causes of cancer-related mortality and morbidity in the aging male population and represents the most frequently diagnosed malignancy in men around the world. The Deltex (DTX)-3-like E3 ubiquitin ligase (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), was originally identified as a binding partner of the diphtheria-toxin-like macrodomain containing ADP-ribosyltransferase-9 (ARTD9), also known as BAL1 and PARP9. We have previously demonstrated that ARTD9 acts as a novel oncogenic survival factor in high-risk, chemo-resistant, diffuse large B cell lymphoma (DLBCL). The mono-ADP-ribosyltransferase ARTD8, also known as PARP14 functions as a STAT6-specific co-regulator of IL4-mediated proliferation and survival in B cells.MethodsCo-expression of DTX3L, ARTD8, ARTD9 and STAT1 was analyzed in the metastatic PCa (mPCa) cell lines PC3, DU145, LNCaP and in the normal prostate luminal epithelial cell lines HPE and RWPE1. Effects on cell proliferation, survival and cell migration were determined in PC3, DU145 and/or LNCaP cells depleted of DTX3L, ARTD8, ARTD9, STAT1 and/or IRF1 compared to their proficient control cells, respectively. In further experiments, real-time RT-PCR, Western blot, immunofluorescence and co-immunoprecipitations were conducted to evaluate the physical and functional interactions between DTX3L, ARTD8 and ARTD9.ResultsHere we could identify DTX3L, ARTD9 and ARTD8 as novel oncogenic survival factors in mPCa cells. Our studies revealed that DTX3L forms a complex with ARTD8 and mediates together with ARTD8 and ARTD9 proliferation, chemo-resistance and survival of mPCa cells. In addition, DTX3L, ARTD8 and ARTD9 form complexes with each other. Our study provides first evidence that the enzymatic activity of ARTD8 is required for survival of mPCa cells. DTX3L and ARTD9 act together as repressors of the tumor suppressor IRF1 in mPCa cells. Furthermore, the present study shows that DTX3L together with STAT1 and STAT3 is implicated in cell migration of mPCa cells.ConclusionsOur data strongly indicate that a crosstalk between STAT1, DTX3L and ARTD-like mono-ADP-ribosyltransferases mediates proliferation and survival of mPCa cells. The present study further suggests that the combined targeted inhibition of STAT1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate and other high-risk tumor types with an increased STAT1 signaling.

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“…Many of these constitutively expressed ISGs have been characterized as antiviral genes (11). Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11)(12)(13)(14)(15)(16)(17)(18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5,9,10,13,19).…”

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confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

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BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-53 axes in diffuse large B-cell lymphoma

Cited by 52 publications

References 58 publications

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

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