E‐cadherin can limit the transforming properties of activating β‐catenin mutations

Huels, David J.; Ridgway, Rachel A.; Radulescu, Sorina; Leushacke, Marc; Campbell, Andrew D.; Biswas, Sujata; Leedham, Simon J.; Serra, Stefano; Chetty, Runjan; Moreaux, Guenièvre; Parry, Lee; Matthews, James R.; Song, Fei; Hedley, Ann; Kalna, Gabriela; Ceteci, Fatih; Reed, Karen Ruth; Méniel, Valérie S.; Maguire, Aoife; Doyle, Brendan; Söderberg, Ola; Barker, Nick; Watson, Alastair; Larue, Lionel; Clarke, Alan R.; Sansom, Owen J.

doi:10.15252/embj.201591739

Cited by 84 publications

(74 citation statements)

References 39 publications

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“…S3C). We also tested axitinib in Apc-deleted murine organoids that grow independently of R-spondin because of β-catenin activation (14). Consistently, axitinib strongly inhibited the growth of Apc-mutant organoids (Fig.…”

Section: Resultsmentioning

confidence: 54%

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Gharbi

Xing

et al. 2016

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

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Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apc min/+ mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.axitinib | β-catenin | asymmetric cell division | SHPRH

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Section: Resultsmentioning

confidence: 54%

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Gharbi

Xing

et al. 2016

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

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“…Silencing of KCNQ1 decreased S33 β-catenin phosphorylation, which enhances β-catenin stability (19). KCNQ1 knockdown increased β-catenin phosphorylation at residues Tyr654 and Ser675, which enhance β-catenin-induced transcription (20,21). Phosphorylation at Tyr654 reduces the β-catenin binding to E-cadherin (22,23), which promotes the association of β-catenin with transcription factors in the nucleus (20).…”

Section: Discussionmentioning

confidence: 99%

“…KCNQ1 knockdown increased β-catenin phosphorylation at residues Tyr654 and Ser675, which enhance β-catenin-induced transcription (20,21). Phosphorylation at Tyr654 reduces the β-catenin binding to E-cadherin (22,23), which promotes the association of β-catenin with transcription factors in the nucleus (20). In addition, P-Ser675 protects β-catenin from proteasomal degradation (24,25).…”

Section: Discussionmentioning

confidence: 99%

Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation

Rapetti-Mauss

Bustos

Thomas

et al. 2017

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

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The K + channel KCNQ1 has been proposed as a tumor suppressor in colorectal cancer (CRC). We investigated the molecular mechanisms regulating KCNQ1:β-catenin bidirectional interactions and their effects on CRC differentiation, proliferation, and invasion. Molecular and pharmacologic approaches were used to determine the influence of KCNQ1 expression on the Wnt/β-catenin signaling and epithelial-to-mesenchymal transition (EMT) in human CRC cell lines of varying stages of differentiation. The expression of KCNQ1 was lost with increasing mesenchymal phenotype in poorly differentiated CRC cell lines as a consequence of repression of the KCNQ1 promoter by β-catenin:T-cell factor (TCF)-4. In welldifferentiated epithelial CRC cell lines, KCNQ1 was localized to the plasma membrane in a complex with β-catenin and E-cadherin. The colocalization of KCNQ1 with adherens junction proteins was lost with increasing EMT phenotype. ShRNA knock-down of KCNQ1 caused a relocalization of β-catenin from the plasma membrane and a loss of epithelial phenotype in CRC spheroids. Overexpression of KCNQ1 trapped β-catenin at the plasma membrane, induced a patent lumen in CRC spheroids, and slowed CRC cell invasion. The KCNQ1 ion channel inhibitor chromanol 293B caused membrane depolarization, redistribution of β-catenin into the cytosol, and a reduced transepithelial electrical resistance, and stimulated CRC cell proliferation. Analysis of human primary CRC tumor patient databases showed a positive correlation between KCNQ1:KCNE3 channel complex expression and disease-free survival. We conclude that the KCNQ1 ion channel is a target gene and regulator of the Wnt/β-catenin pathway, and its repression leads to CRC cell proliferation, EMT, and tumorigenesis.T he development of colorectal cancer (CRC) is determined by multiple factors including ion transport (1, 2). During the last 10 years, evidence for the role of K + channels in the development and growth of tumors has greatly expanded. Voltage-gated K + channels (Kv) are involved in the proliferation of many cell types, including intestinal cells. Although the recent literature clearly demonstrates that Kv channels are among the targets of interest in the fight against cancer (3-5), the specific role of each Kv channel in tumorigenesis and the molecular mechanisms involved are unknown. This is notably the case of the KCNQ1 K + channel. The KCNQ1 gene has recently been identified as a tumor suppressor in mouse and human CRC tissues (6). KCNQ1 deficiency in mice caused rectal adenomatous hyperplasia and progression to adenocarcinoma. A loss of imprinting of KCNQ1 has been described in CRC (7). However, the functional and molecular events linking KCNQ1 and CRC progression remain unclear. One obvious pathway, which may interact with KCNQ1, is Wnt/ β-catenin signaling, which plays a key role in driving early embryogenesis, as well as intestinal homeostasis and stem cell renewal in the intestinal mucosa epithelia (8). Deregulation of the β-catenin signaling axis is present in more than 80% of CRC...

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“…the epithelial-to-mesenchymal transition (EMT) 72,73,74 . The down-regulation of E-Cadherin (usually tightly associated with β-catenin in normal epithelium) triggers the nuclear translocation of β-catenin and activation of canonical Wnt signaling 75 . The gene slug, a marker gene of EMT, also induces nuclear translocation of β-catenin 76,76 .…”

Section: ) the Role Of Wnt Signaling In Cancer Stem Cellsmentioning

confidence: 99%

The Wnt signaling pathway in cancer

Duchartre

Kim

Kahn

2016

Critical Reviews in Oncology/Hematology

435

344

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The Wnt signaling pathway is critically involved in both the development and homeostasis of tissues via regulation of their endogenous stem cells. Aberrant Wnt signaling has been described as a key player in the initiation of and/or maintenance and development of many cancers, via affecting the behavior of Cancer Stem Cells (CSCs). CSCs are considered by most to be responsible for establishment of the tumor and also for disease relapse, as they possess inherent drug-resistance properties. The development of new therapeutic compounds targeting the Wnt signaling pathway promises new hope to eliminate CSCs and achieve cancer eradication. However, a major challenge resides in developing a strategy efficient enough to target the dysregulated Wnt pathway in CSCs, while being safe enough to not damage the normal somatic stem cell population required for tissue homeostasis and repair. Here we review recent therapeutic approaches to target the Wnt pathway and their clinical applications.

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E‐cadherin can limit the transforming properties of activating β‐catenin mutations

Cited by 84 publications

References 39 publications

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Bidirectional KCNQ1:β-catenin interaction drives colorectal cancer cell differentiation

The Wnt signaling pathway in cancer

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