Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts
Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-03-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/13/7/608 |
| _version_ | 1827286919188316160 |
|---|---|
| author | Maria Michela Pallotta Maddalena Di Nardo Antonio Musio |
| author_facet | Maria Michela Pallotta Maddalena Di Nardo Antonio Musio |
| author_sort | Maria Michela Pallotta |
| collection | DOAJ |
| description | Cohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased interest in cohesin as a potential target in cancer therapy. Synthetic lethality has been suggested as an approach to exploit genetic differences in cancer cells to influence their selective killing. In this study, we show that mutations in <i>ESCO1</i>, <i>NIPBL</i>, <i>PDS5B</i>, <i>RAD21</i>, <i>SMC1A</i>, <i>SMC3</i>, <i>STAG2</i>, and <i>WAPL</i> genes are synthetically lethal with stimulation of WNT signaling obtained following LY2090314 treatment, a GSK3 inhibitor, in several cancer cell lines. Moreover, treatment led to the stabilization of β-catenin and affected the expression of <i>c-MYC,</i> probably due to the occupancy decrease in cohesin at the <i>c-MYC</i> promoter. Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin. |
| first_indexed | 2024-04-24T10:48:08Z |
| format | Article |
| id | doaj.art-b52750eaa6894a518c5c106ebd7b0436 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-04-24T10:48:08Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-b52750eaa6894a518c5c106ebd7b04362024-04-12T13:16:32ZengMDPI AGCells2073-44092024-03-0113760810.3390/cells13070608Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer ContextsMaria Michela Pallotta0Maddalena Di Nardo1Antonio Musio2Institute for Biomedical Technologies (ITB), National Research Council (CNR), 56124 Pisa, ItalyInstitute for Biomedical Technologies (ITB), National Research Council (CNR), 56124 Pisa, ItalyInstitute for Biomedical Technologies (ITB), National Research Council (CNR), 56124 Pisa, ItalyCohesin is a highly conserved ring-shaped complex involved in topologically embracing chromatids, gene expression regulation, genome compartmentalization, and genome stability maintenance. Genomic analyses have detected mutations in the cohesin complex in a wide array of human tumors. These findings have led to increased interest in cohesin as a potential target in cancer therapy. Synthetic lethality has been suggested as an approach to exploit genetic differences in cancer cells to influence their selective killing. In this study, we show that mutations in <i>ESCO1</i>, <i>NIPBL</i>, <i>PDS5B</i>, <i>RAD21</i>, <i>SMC1A</i>, <i>SMC3</i>, <i>STAG2</i>, and <i>WAPL</i> genes are synthetically lethal with stimulation of WNT signaling obtained following LY2090314 treatment, a GSK3 inhibitor, in several cancer cell lines. Moreover, treatment led to the stabilization of β-catenin and affected the expression of <i>c-MYC,</i> probably due to the occupancy decrease in cohesin at the <i>c-MYC</i> promoter. Finally, LY2090314 caused gene expression dysregulation mainly involving pathways related to transcription regulation, cell proliferation, and chromatin remodeling. For the first time, our work provides the underlying molecular basis for synthetic lethality due to cohesin mutations and suggests that targeting the WNT may be a promising therapeutic approach for tumors carrying mutated cohesin.https://www.mdpi.com/2073-4409/13/7/608cohesinWNTβ-catenincancersynthetic lethalityLY2090314 |
| spellingShingle | Maria Michela Pallotta Maddalena Di Nardo Antonio Musio Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts Cells cohesin WNT β-catenin cancer synthetic lethality LY2090314 |
| title | Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts |
| title_full | Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts |
| title_fullStr | Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts |
| title_full_unstemmed | Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts |
| title_short | Synthetic Lethality between Cohesin and WNT Signaling Pathways in Diverse Cancer Contexts |
| title_sort | synthetic lethality between cohesin and wnt signaling pathways in diverse cancer contexts |
| topic | cohesin WNT β-catenin cancer synthetic lethality LY2090314 |
| url | https://www.mdpi.com/2073-4409/13/7/608 |
| work_keys_str_mv | AT mariamichelapallotta syntheticlethalitybetweencohesinandwntsignalingpathwaysindiversecancercontexts AT maddalenadinardo syntheticlethalitybetweencohesinandwntsignalingpathwaysindiversecancercontexts AT antoniomusio syntheticlethalitybetweencohesinandwntsignalingpathwaysindiversecancercontexts |