3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer
Cadherins are cell–cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. <i>CDH1</i> and <i&g...
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MDPI AG
2023-05-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/12/6/803 |
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| author | Celina São José Carla Pereira Marta Ferreira Ana André Hugo Osório Irene Gullo Fátima Carneiro Carla Oliveira |
| author_facet | Celina São José Carla Pereira Marta Ferreira Ana André Hugo Osório Irene Gullo Fátima Carneiro Carla Oliveira |
| author_sort | Celina São José |
| collection | DOAJ |
| description | Cadherins are cell–cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. <i>CDH1</i> and <i>CDH3</i> mRNA expression was obtained from 42 gastric tumours’ RNA-seq data. CRISPR-Cas9 was used to knock out <i>CDH1</i> and a putative regulatory element. <i>CDH1</i>-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a <i>CDH1</i> promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess <i>CDH1</i>/E-cadherin and <i>CDH3</i>/P-cadherin expression. In 42% of gastric tumours analysed, <i>CDH1</i> to <i>CDH3</i> switch was observed. <i>CDH1</i> knockout triggered <i>CDH1</i>/E-cadherin complete loss and <i>CDH3</i>/P-cadherin expression increase at plasma membrane. This switch, likely rescuing adherens junctions, increased cell migration/proliferation, commonly observed in aggressive tumours. E- to P-cadherin switch accompanied increased <i>CDH1</i> promoter interactions with <i>CDH3</i>–eQTL, absent in normal stomach and parental cells. <i>CDH3</i>–eQTL deletion promotes <i>CDH3</i>/<i>CDH1</i> reduced expression. These data provide evidence that loss of <i>CDH1</i>/E-cadherin expression alters the <i>CDH3</i> locus chromatin conformation, allowing a <i>CDH1</i> promoter interaction with a <i>CDH3</i>-eQTL, and promoting <i>CDH3</i>/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer. |
| first_indexed | 2024-03-11T02:46:03Z |
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| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-11T02:46:03Z |
| publishDate | 2023-05-01 |
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| spelling | doaj.art-c19885064bef47109799dff3020fb63c2023-11-18T09:22:47ZengMDPI AGBiology2079-77372023-05-0112680310.3390/biology120608033D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric CancerCelina São José0Carla Pereira1Marta Ferreira2Ana André3Hugo Osório4Irene Gullo5Fátima Carneiro6Carla Oliveira7Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalInstituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalCadherins are cell–cell adhesion molecules, fundamental for cell architecture and polarity. E-cadherin to P-cadherin switch can rescue adherens junctions in epithelial tumours. Herein, we disclose a mechanism for E-cadherin to P-cadherin switch in gastric cancers. <i>CDH1</i> and <i>CDH3</i> mRNA expression was obtained from 42 gastric tumours’ RNA-seq data. CRISPR-Cas9 was used to knock out <i>CDH1</i> and a putative regulatory element. <i>CDH1</i>-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a <i>CDH1</i> promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess <i>CDH1</i>/E-cadherin and <i>CDH3</i>/P-cadherin expression. In 42% of gastric tumours analysed, <i>CDH1</i> to <i>CDH3</i> switch was observed. <i>CDH1</i> knockout triggered <i>CDH1</i>/E-cadherin complete loss and <i>CDH3</i>/P-cadherin expression increase at plasma membrane. This switch, likely rescuing adherens junctions, increased cell migration/proliferation, commonly observed in aggressive tumours. E- to P-cadherin switch accompanied increased <i>CDH1</i> promoter interactions with <i>CDH3</i>–eQTL, absent in normal stomach and parental cells. <i>CDH3</i>–eQTL deletion promotes <i>CDH3</i>/<i>CDH1</i> reduced expression. These data provide evidence that loss of <i>CDH1</i>/E-cadherin expression alters the <i>CDH3</i> locus chromatin conformation, allowing a <i>CDH1</i> promoter interaction with a <i>CDH3</i>-eQTL, and promoting <i>CDH3</i>/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.https://www.mdpi.com/2079-7737/12/6/803gastric cancercadherins switchregulatory elements3D chromatin architecturechromatin interactionsCDH1 |
| spellingShingle | Celina São José Carla Pereira Marta Ferreira Ana André Hugo Osório Irene Gullo Fátima Carneiro Carla Oliveira 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer Biology gastric cancer cadherins switch regulatory elements 3D chromatin architecture chromatin interactions CDH1 |
| title | 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer |
| title_full | 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer |
| title_fullStr | 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer |
| title_full_unstemmed | 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer |
| title_short | 3D Chromatin Architecture Re-Wiring at the <i>CDH3/CDH1</i> Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer |
| title_sort | 3d chromatin architecture re wiring at the i cdh3 cdh1 i loci contributes to e cadherin to p cadherin expression switch in gastric cancer |
| topic | gastric cancer cadherins switch regulatory elements 3D chromatin architecture chromatin interactions CDH1 |
| url | https://www.mdpi.com/2079-7737/12/6/803 |
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