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Genome-wide CRISPR/Cas9 screening identifies a targetable MEST-PURA interaction in cancer metastasis. | LitMetric

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

EBioMedicine

Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes and Key Laboratory of Protein Modification and Degradation, The Fifth Affiliated Hospital of Guangzhou Medical University and School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China; MOE Key Laboratory of Tumor Molecular Biology, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China. Electronic address:

Published: June 2023

AI Article Synopsis

  • Metastasis in esophageal squamous cell carcinoma (ESCC) is a major challenge due to unclear mechanisms and lack of effective therapeutic models, necessitating research into its drivers.
  • Utilizing CRISPR/Cas9 screening and various genetic profiling techniques, researchers identified MEST as a key regulator of metastasis, linked to poor patient survival through its influence on specific signaling pathways.
  • The study emphasizes targeting the MEST-PURA interaction to inhibit cancer metastasis, highlighting miR-449a as a potential therapeutic agent and identifying G699-0288 as a promising compound for treatment.

Article 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.

Funding: This work was supported by National Key Research and Development Program of China (2021YFC2501000, 2021YFC2501900, 2017YFA0505100); National Natural Science Foundation of China (31961160727, 82073196, 81973339, 81803551); NSFC/RGC Joint Research Scheme (N_HKU727/19); Natural Science Foundation of Guangdong Province (2021A1515011158, 2021A0505030035); Key Laboratory of Guangdong Higher Education Institutes of China (2021KSYS009).

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10192437PMC
http://dx.doi.org/10.1016/j.ebiom.2023.104587DOI Listing

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