Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of<i>CDX1</i>and<i>EPHB</i>tumor suppressor genes in colorectal cancer

Rönsch, Kerstin; Jäger, Marcel; Schöpflin, Anja; Danciu, Mihai; Laßmann, Silke; Hecht, Andreas

doi:10.4161/epi.6.5.15300

Cited by 26 publications

(26 citation statements)

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“…S1A) and that faithfully reflect the variable levels of EPHB3 expression seen in human CRC tissue specimens (Fig. 1B) (4). In these experiments, the presence of the ECR centered around −2.3 kb strongly increased reportergene activity (Fig.…”

Section: Resultsmentioning

confidence: 67%

“…Nonetheless, this study and previous work showed that molecular details of EPHB2/EPHB3 inactivation differ (4). Wnt/β-catenin activity is one of the drivers of EPHB2/EPHB3 expression and likely accounts for their upregulation in colorectal adenomas (31).…”

Section: Discussionmentioning

confidence: 98%

“…EPHB2 and EPHB3 show similar expression changes during colorectal-cancer progression (1,4), and secondary down-regulation of both genes seemingly involves the inactivation of promoter-distal enhancers. Nonetheless, this study and previous work showed that molecular details of EPHB2/EPHB3 inactivation differ (4).…”

Section: Discussionmentioning

confidence: 99%

“…In colorectal tumors, EPHB3 exhibits biphasic expression profiles that are distinguished by a surge in expression in adenomas and secondary down-regulation in carcinomas (1,2,4). EPHB3 is a direct target of Wnt/β-catenin signaling (9), which may explain EPHB3 up-regulation in early tumorigenesis.…”

mentioning

confidence: 99%

“…In addition, EPHB/EphrinB signaling affects the function of the cell-cell adhesion molecule E-cadherin, thereby adding to the stabilization of a noninvasive epithelial-cell phenotype (3). However, colorectal carcinomas frequently overcome the invasion/tumor suppressor function of the EPHB/EphrinB system by transcriptional down-regulation of receptor expression (1,2,4).…”

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confidence: 99%

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Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer

Jägle

Rönsch

Timme

et al. 2014

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

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The protein tyrosine kinase Ephrin type-B receptor 3 (EPHB3) counteracts tumor-cell dissemination by regulating intercellular adhesion and repulsion and acts as tumor/invasion suppressor in colorectal cancer. This protective mechanism frequently collapses at the adenoma-carcinoma transition due to EPHB3 transcriptional silencing. Here, we identify a transcriptional enhancer at the EPHB3 gene that integrates input from the intestinal stem-cell regulator achaete-scute family basic helix-loop-helix transcription factor 2 (ASCL2), Wnt/β-catenin, MAP kinase, and Notch signaling. EPHB3 enhancer activity is highly variable in colorectal carcinoma cells and precisely reflects EPHB3 expression states, suggesting that enhancer dysfunction underlies EPHB3 silencing. Interestingly, low Notch activity parallels reduced EPHB3 expression in colorectal carcinoma cell lines and poorly differentiated tumor-tissue specimens. Restoring Notch activity reestablished enhancer function and EPHB3 expression. Although essential for intestinal stem-cell maintenance and adenoma formation, Notch activity seems dispensable in colorectal carcinomas. Notch activation even promoted growth arrest and apoptosis of colorectal carcinoma cells, attenuated their self-renewal capacity in vitro, and blocked tumor growth in vivo. Higher levels of Notch activity also correlated with longer disease-free survival of colorectal cancer patients. In summary, our results uncover enhancer decommissioning as a mechanism for transcriptional silencing of the EPHB3 tumor suppressor and argue for an antitumorigenic function of Notch signaling in advanced colorectal cancer.tumor progression | metastasis | Ephrin signaling | EPHB2

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Section: Resultsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer

Jägle

Rönsch

Timme

et al. 2014

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

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The Eph Receptor Family

Gaitanos

Dudanova

Σάκκου

et al. 2015

Receptor Tyrosine Kinases: Family and Subfamilies

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Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases

Hirsch¹,

Martin-Lannerée²,

Reine³

et al. 2018

Mol Neurobiol

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Among the ever-growing number of self-replicating proteins involved in neurodegenerative diseases, the prion protein PrP remains the most infamous for its central role in transmissible spongiform encephalopathies (TSEs). In these diseases, pathogenic prions propagate through a seeding mechanism, where normal PrP molecules are converted into abnormally folded scrapie isoforms termed PrP. Since its discovery over 30 years ago, much advance has contributed to define the host-encoded cellular prion protein PrP as a critical relay of prion-induced neuronal cell demise. A current consensual view is that the conversion of PrP into PrP in neuronal cells diverts the former from its normal function with subsequent molecular alterations affecting synaptic plasticity. Here, we report that prion infection is associated with reduced expression of key effectors of the Notch pathway in vitro and in vivo, recapitulating changes fostered by the absence of PrP. We further show that both prion infection and PrP depletion promote drastic alterations in the expression of a defined set of Eph receptors and their ephrin ligands, which represent important players in synaptic function. Our data indicate that defects in the Notch and Eph axes can be mitigated in response to histone deacetylase inhibition in PrP-depleted as well as prion-infected cells. We thus conclude that infectious prions cause a loss-of-function phenotype with respect to Notch and Eph signaling and that these alterations are sustained by epigenetic mechanisms.

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Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing ofCDX1andEPHBtumor suppressor genes in colorectal cancer

Cited by 26 publications

References 50 publications

Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer

Silencing of the EPHB3 tumor-suppressor gene in human colorectal cancer through decommissioning of a transcriptional enhancer

The Eph Receptor Family

Epigenetic Control of the Notch and Eph Signaling Pathways by the Prion Protein: Implications for Prion Diseases

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