The Symplekin/ZONAB Complex Inhibits Intestinal Cell Differentiation by the Repression of AML1/Runx1

Büchert, Michael; Darido, Charbel; Lagerqvist, Ebba L.; Sedello, Anna; Cazevieille, Chantal; Buchholz, Frank; Bourgaux, Jean–François; Pannequin, Julie; Joubert, Dominique; Hollande, Frédéric

doi:10.1053/j.gastro.2009.03.037

Cited by 33 publications

(35 citation statements)

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“…In this study, we detected a high level of symplekin expression in the nucleus of human CRC cells, similar to that recently detected in the proliferative compartment at the bottom of healthy colonic crypts (13). We also demonstrated that symplekin down-regulation in CRC cells reduces their tumorigenicity in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 59%

“…We also demonstrated that symplekin down-regulation in CRC cells reduces their tumorigenicity in vitro and in vivo. This effect probably is related to the role of symplekin as a transcriptional cofactor in the nucleus, where it modulates the expression of genes involved in proliferation and stress responses in vitro (6,12) and inhibits intestinal differentiation in vivo (13). In addition, symplekin down-regulation promotes polarization in CRC cells, strongly suggesting that symplekin overexpression in these cells also plays an active part in the disruption of tissue homeostasis by disrupting epithelial cell organization, resulting in a promotion of tumor progression.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, nuclear staining for symplekin was restricted largely to the bottom half of colonic crypts in the macroscopically healthy epithelium, as described in ref. 13 and shown in Fig. S1.…”

Section: Resultsmentioning

confidence: 99%

“…Processing and observation of samples for transmission electron microscopy was performed as described in ref. 13. …”

Section: Methodsmentioning

confidence: 99%

“…It is involved in the nuclear premRNA cleavage and polyadenylation machinery (8)(9)(10)(11), and we and others recently reported a direct interaction of symplekin with two transcription factors, ZONAB/DbpA and heat shock factor protein 1 (HSF1) (6,12). The functional interaction between symplekin and ZONAB/DbpA promotes proliferation (6) and acts as a negative modulator of goblet-cell differentiation in the intestine (13). However, despite its partial TJ localization, nothing currently is known about a potential role of symplekin in cell polarization.…”

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confidence: 99%

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Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

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

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Symplekin is a ubiquitously expressed protein involved in cytoplasmic RNA polyadenylation and transcriptional regulation and is localized at tight junctions (TJs) in epithelial cells. Nuclear symplekin cooperates with the Y-box transcription factor zonula occludens 1-associated nucleic acid-binding protein (ZONAB) to increase the transcription of cell cycle-related genes and also inhibits differentiation of intestinal cells. We detected high levels of nuclear symplekin in 8 of 12 human colorectal cancer (CRC) samples. shRNAmediated reduction of symplekin expression was sufficient to decrease significantly the anchorage-independent growth and proliferation of HT-29 CRC cells as well as their tumorigenicity when injected into immunodeficient animals. Symplekin downregulation also was found to alter ion transport through TJs, to promote the localization of ZONAB in the membrane rather than the nucleus, and strongly to enhance cell polarization in a 3D matrix, leading to the formation of spheroids organized around a central lumen. Claudin-2 expression was reduced following symplekin down-regulation, an effect mimicked when ZONAB expression was down-regulated using selective siRNA. Virus-mediated restoration of claudin-2 expression was found to restore nuclear expression of ZONAB in HT29ΔSym cells and to rescue the phenotypic alterations induced by symplekin down-regulation of cell polarity, paracellular transport, ZONAB localization, cyclin D1 expression, proliferation, and anchorage-independent growth. Finally, siRNA-mediated claudin-2 down-regulation increased the transepithelial resistance and decreased cyclin D1 expression and ZONAB nuclear localization, similar to observations in symplekindepleted cells. Our results suggest that nuclear overexpression of symplekin promotes tumorigenesis in the human colon and that the regulation of claudin-2 expression is instrumental in this effect.polarity | transcription | tumorigenesis | colorectal | tight junctions

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Processing and observation of samples for transmission electron microscopy was performed as described in ref. 13. …”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Büchert

Papin

Bonnans

et al. 2010

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

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Ral signaling pathway in health and cancer

et al. 2017

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The Ral (Ras‐Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

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Novel colon cancer susceptibility variants identified from a genome‐wide association study in African Americans

Wang

Schmit

Haiman

et al. 2017

Intl Journal of Cancer

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Genome-wide association studies (GWAS) in ethnic/racial minority populations can help to fine-map previously identified risk regions or discover new risk loci because of the genetic diversity in these populations. We conducted a GWAS of colorectal cancer (CRC) in 6,597 African Americans (1,894 cases and 4,703 controls) (Stage 1) and followed up the most promising markers in a replication set of 2,041 participants of African descent (891 cases and 1,150 controls) (Stage 2). We identified a novel variant, rs56848936 in the gene SYMPK at 19q13.3, associated with colon cancer risk (odds ratio 0.61 for the risk allele G, P = 2.4 × 10−8). The frequency of the G allele was 0.06 in African Americans, compared to <0.01 in Europeans, Asians and Amerindians in the 1000 Genomes project. In addition, a variant previously identified through fine-mapping in this GWAS in the region 19q13.1, rs7252505, was confirmed to be more strongly associated with CRC in the African American replication set than the variant originally reported in Europeans (rs10411210). The association between rs7252505 and CRC was of borderline significance (P = 0.05) in a Hispanic population GWAS with 1,611 CRC cases and 4,330 controls. With the three datasets combined, the odds ratio was 0.84 for the risk allele A (95% confidence interval 0.79–0.89, P = 3.7 × 10−8). This study further highlights the importance of conducting GWAS studies in diverse ancestry populations.

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The Symplekin/ZONAB Complex Inhibits Intestinal Cell Differentiation by the Repression of AML1/Runx1

Cited by 33 publications

References 30 publications

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Symplekin promotes tumorigenicity by up-regulating claudin-2 expression

Ral signaling pathway in health and cancer

Novel colon cancer susceptibility variants identified from a genome‐wide association study in African Americans

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