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  The Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer

Franke, F. C., Müller, J., Abal, M., Medina, E. D., Nitsche, U., Weidmann, H., et al. (2019). The Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 7(1), 33-53. doi:10.1016/j.jcmgh.2018.08.007.

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 Creators:
Franke, Fabian Christoph1, Author
Müller, Johannes2, Author              
Abal, Miguel1, Author
Medina, Eduardo Dominguez1, Author
Nitsche, Ulrich1, Author
Weidmann, Henri1, Author
Chardonnet, Solenne1, Author
Ninio, Ewa1, Author
Janssen, Klaus-Peter1, Author
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1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: FOCAL ADHESIONS; PROTEIN; EMT; GENE; ORGANIZATION; INVASION; FAMILY; CELLS; GAB1; HGFGastroenterology & Hepatology; EMT; Tumor Suppressor; SRC-Kinase; Chemoresistance;
 Abstract: This study showed a metastasis-suppressive function of sterile a motif-and Src-homology 3-domain containing 1 (SASH1) in vivo. Furthermore, SASH1 antagonizes epithelial-mesenchymal transition, tumor aggressiveness, and chemoresistance in colon cancer. Mechanistically, SASH1 directly inhibits the oncoprotein V-Crk avian sarcoma virus CT10 oncogene homolog-like, introduced as its new interaction partner. BACKGROUND & AIMS: The tumor-suppressor sterile a motifand Src-homology 3-domain containing 1 (SASH1) has clinical relevance in colorectal carcinoma and is associated specifically with metachronous metastasis. We sought to identify the molecular mechanisms linking decreased SASH1 expression with distant metastasis formation. METHODS: SASH1-deficient, SASH1-depleted, or SASH1overexpressing HCT116 colon cancer cells were generated by the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9-method, RNA interference, and transient plasmid transfection, respectively. Epithelialmesenchymal transition (EMT) was analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblotting, immunofluorescence microscopy, migration/invasion assays, and 3-dimensional cell culture. Yeast 2-hybrid assays and co-immunoprecipitation/mass-spectrometry showed V-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) as a novel interaction partner of SASH1, further confirmed by domain mapping, site-directed mutagenesis, co-immunoprecipitation, and dynamic mass redistribution assays. CRKL-deficient cells were generated in parental or SASH1-deficient cells. Metastatic capacity was analyzed with an orthotopic mouse model. Expression and significance of SASH1 and CRKL for survival and response to chemotherapy was assessed in patient samples from our department and The Cancer Genome Atlas data set. RESULTS: SASH1 expression is down-regulated during cytokine-induced EMT in cell lines from colorectal, pancreatic, or hepatocellular cancer, mediated by the putative SASH1 promoter. Deficiency or knock-down of SASH1 induces EMT, leading to an aggressive, invasive phenotype with increased chemoresistance. SASH1 counteracts EMT through interaction with the oncoprotein CRKL, inhibiting CRKL-mediated activation of SRC kinase, which is crucially required for EMT. SASH1-deficient cells form significantly more metastases in vivo, depending entirely on CRKL. Patient tumor samples show significantly decreased SASH1 and increased CRKL expression, associated with significantly decreased overall survival. Patients with increased CRKL expression show significantly worse response to adjuvant chemotherapy. CONCLUSIONS: We propose SASH1 as an inhibitor of CRKL-mediated SRC signaling, introducing a potentially druggable mechanism counteracting chemoresistance and metastasis formation.

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Language(s): eng - English
 Dates: 2019
 Publication Status: Published in print
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
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Title: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Source Genre: Journal
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Publ. Info: 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA : ELSEVIER INC
Pages: - Volume / Issue: 7 (1) Sequence Number: - Start / End Page: 33 - 53 Identifier: ISSN: 2352-345X