Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Ladang, Aurélie; Rapino, Francesca; Heukamp, Lukas C.; Tharun, Lars; Shostak, Kateryna; Hermand, Damien; Delaunay, Sylvain; Klevernic, Iva; Jiang, Zheshen; Jacques, Nicolas; Jamart, Diane; Migeot, Valérie; Florin, Alexandra; Göktuna, Serkan Ismail; Malgrange, Brigitte; Sansom, Owen J.; Nguyen, Laurent; Büttner, Reinhard; Close, Pierre; Chariot, Alain

doi:10.1083/jcb.2113oia257

Cited by 13 publications

(21 citation statements)

References 25 publications

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“…ELP3 is induced by Wnt signaling and promotes SOX9 translation, which is necessary for maintenance of intestinal cancer stem cells , and SOX9 is upregulated in stem cell population in tongue SCC cells . Furthermore, ELP3 maintains genomic stability and regulates DNA replication and DNA repair by directly interacting with PCNA, which may also recruit the elongator complex to modulate chromatin structure during DNA replication or in response to DNA damage .…”

Section: Resultsmentioning

confidence: 99%

Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization

et al. 2017

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Oral squamous cell carcinoma (OSCC) develops through a multistep carcinogenic process involving field cancerization. The DEK gene is a proto‐oncogene with functions in genetic and epigenetic modifications, and has oncogenic functions, including cellular proliferation, differentiation, and senescence. DEK overexpression is associated with malignancies; however, the functional roles of DEK overexpression are unclear. We demonstrated that DEK‐expressing cells were significantly increased in human dysplasia/carcinoma in situ and OSCC. Furthermore, we generated ubiquitous and squamous cell‐specific doxycycline (DOX)‐inducible Dek mice (iDek and iDek‐e mice respectively). Both DOX+ iDek and iDek‐e mice did not show differences in the oral mucosa compared with DOX‐ mice. In the environment exposed to carcinogen, DOX‐treated (DOX+) iDek mice showed field cancerization and OSCC development. Microarray analysis revealed that DEK overexpression was mediated by the upregulation of DNA replication‐ and cell cycle‐related genes, particularly those related to the G 1/S transition. Tongue tumors overexpressing DEK showed increased proliferating cell nuclear antigen and elongator complex protein 3 expression. Our data suggest that DEK overexpression enhanced carcinogenesis, including field cancerization, in OSCC by stimulating the G 1/S phase transition and promoting DNA replication, providing important insights into the potential applications of DEK as a target in the treatment and prevention of OSCC.

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Section: Resultsmentioning

confidence: 99%

Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization

et al. 2017

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“…Intestinal crypts from Apc þ/min -Ikke À/À and Apc þ/min -Ikke þ/þ mice were isolated and cultured as described (31). Stimulations of ex vivo organoid cultures with IL17A and LPS were carried out as described (9).…”

Section: Ex Vivo Organoid Culturesmentioning

confidence: 99%

The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine

et al. 2016

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Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikke in Wnt-driven tumor development. We found that Ikke was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikke in b-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikke to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikke was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding proinflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikke-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikke phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikke to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9);

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“…Elp3 conditional knockout mice were generated by backcrossing Elp3loxp/loxp [29,31] into the MF1 background of Dlx 5,6:Cre-GFP (Dr K Campbell, Cincinnati, USA) for selected experiments and housed under standard conditions at the GIGA-Mouse facility and Transgenics, University of Liège. All animals were treated according to the guidelines of the Belgian Ministry of Agriculture in agreement with European community Laboratory Animal Care and Use Regulations (86/609/CEE, Journal Officiel des Communautées Européennes, L358, 18 December 1986).…”

Section: Animalsmentioning

confidence: 99%

“…Its nuclear roles include transcription elongation [24,25] and paternal genome demethylation [23]. In contrast, its main cytoplasmic role, described in yeast [26][27][28] and in mammals [29], is the promotion of tRNA modifications at the first nucleotide anticodon U34 (Elongator belongs to tRAMEs, an enzymatic cascade that promotes U34 tRNA anticodon side chain modifications) [30], thereby controlling mRNA translational efficiency in health [27] and disease [31]. Loss of Elongator activity leads to slowdown of translation resulting in proteotoxic stress [27].…”

Section: Introductionmentioning

confidence: 99%

Elongator controls cortical interneuron migration by regulating actomyosin dynamics

et al. 2016

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The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.

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Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine

Cited by 13 publications

References 25 publications

Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization

Promotion of cell proliferation by the proto‐oncogene DEK enhances oral squamous cell carcinogenesis through field cancerization

The Prosurvival IKK-Related Kinase IKKϵ Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine

Elongator controls cortical interneuron migration by regulating actomyosin dynamics

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