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Article: Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis

TitleGenome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis
Authors
KeywordsCancer metastasis
CRISPR/Cas9 screening
Esophageal cancer
Noncoding RNA
Protein interactome
Issue Date4-May-2023
PublisherElsevier
Citation
EBioMedicine, 2023, v. 92 How to Cite?
Abstract

Background

Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease.

Methods

A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis.

Findings

High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis.

Interpretation

We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis.


Persistent Identifierhttp://hdl.handle.net/10722/340844
ISSN
2023 Impact Factor: 9.7
2023 SCImago Journal Rankings: 3.193
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWen, W-
dc.contributor.authorLiao, L-
dc.contributor.authorDai, W-
dc.contributor.authorZheng, CC-
dc.contributor.authorTan, XP-
dc.contributor.authorHe, Y-
dc.contributor.authorZhang, QH-
dc.contributor.authorHuang, ZH-
dc.contributor.authorChen, WY-
dc.contributor.authorQin, YR-
dc.contributor.authorChen, KS-
dc.contributor.authorHe, ML-
dc.contributor.authorLaw, S-
dc.contributor.authorLung, ML-
dc.contributor.authorHe, QY-
dc.contributor.authorLi, B -
dc.date.accessioned2024-03-11T10:47:43Z-
dc.date.available2024-03-11T10:47:43Z-
dc.date.issued2023-05-04-
dc.identifier.citationEBioMedicine, 2023, v. 92-
dc.identifier.issn2352-3964-
dc.identifier.urihttp://hdl.handle.net/10722/340844-
dc.description.abstract<h3>Background</h3><p>Metastasis is one of the most lethal hallmarks of esophageal squamous cell carcinoma (ESCC), yet the mechanisms remain unclear due to a lack of reliable experimental models and systematic identification of key drivers. There is urgent need to develop useful therapies for this lethal disease.</p><h3>Methods</h3><p>A genome-wide CRISPR/Cas9 screening, in combination with gene profiling of highly invasive and metastatic ESCC sublines, as well as PDX models, was performed to identify key regulators of cancer metastasis. The Gain- and loss-of-function experiments were taken to examine gene function. Protein interactome, RNA-seq, and whole genome methylation sequencing were used to investigate gene regulation and molecular mechanisms. Clinical significance was analyzed in tumor tissue microarray and TCGA databases. Homology modeling, modified ELISA, surface plasmon resonance and functional assays were performed to identify lead compound which targets MEST to suppress cancer metastasis.</p><h3>Findings</h3><p>High MEST expression was associated with poor patient survival and promoted cancer invasion and metastasis in ESCC. Mechanistically, MEST activates SRCIN1/RASAL1-ERK-snail signaling by interacting with PURA. miR-449a was identified as a direct regulator of MEST, and hypermethylation of its promoter led to MEST upregulation, whereas systemically delivered miR-449a mimic could suppress tumor metastasis without overt toxicity. Furthermore, molecular docking and computational screening in a small-molecule library of 1,500,000 compounds and functional assays showed that G699-0288 targets the MEST-PURA interaction and significantly inhibits cancer metastasis.</p><h3>Interpretation</h3><p>We identified the MEST-PURA-SRCIN1/RASAL1-ERK-snail signaling cascade as an important mechanism underlying cancer metastasis. Blockade of MEST-PURA interaction has therapeutic potential in management of cancer metastasis.</p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofEBioMedicine-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCancer metastasis-
dc.subjectCRISPR/Cas9 screening-
dc.subjectEsophageal cancer-
dc.subjectNoncoding RNA-
dc.subjectProtein interactome-
dc.titleGenome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis-
dc.typeArticle-
dc.identifier.doi10.1016/j.ebiom.2023.104587-
dc.identifier.scopuseid_2-s2.0-85154613971-
dc.identifier.volume92-
dc.identifier.eissn2352-3964-
dc.identifier.isiWOS:001002835700001-
dc.identifier.issnl2352-3964-

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