Portal de investigação
3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- José, CS
- Pereira, C
- Ferreira, M
- Andr?, A
- Osório, H
- Oliveira, C
Unidades de investigação
Abstract
Simple Summary The cell architecture is created and maintained via adhesion molecules, called cadherins, that keep similar cells bound to each other. E-cadherin is a cadherin encoded by the CDH1 gene, essential in normal epithelia. P-cadherin, encoded by the CDH3 gene, exerts a similar function but is mainly present in tumours. E- to P-cadherin switch is a common event in several epithelial tumours. We unveiled a mechanism explaining the E- to P-cadherin switch (CDH1 to CDH3 switch), which we found to occur in many gastric cancers. We induced this switch by depleting CDH1 in gastric cancer cells, and, as they started to produce CDH3, this rescued cell-adhesion. Despite this rescue, cells bearing the switch showed migratory and proliferative features, commonly observed in aggressive tumours. We observed that CDH1 depletion leads to novel genomic interactions between the CDH1 and CDH3 gene sequences. We identified the sequences needed for these interactions to occur, which seem also responsible for controlling the amount of E- or P-cadherin molecules in the cell. Our data provide evidence that loss of E-cadherin is able to compromise the normal interactions between the CDH1 to CDH3 gene sequences, allowing the expression of P-cadherin in gastric cancers. 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. CDH1 and CDH3 mRNA expression was obtained from 42 gastric tumours' RNA-seq data. CRISPR-Cas9 was used to knock out CDH1 and a putative regulatory element. CDH1-depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a CDH1 promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess CDH1/E-cadherin and CDH3/P-cadherin expression. In 42% of gastric tumours analysed, CDH1 to CDH3 switch was observed. CDH1 knockout triggered CDH1/E-cadherin complete loss and CDH3/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 CDH1 promoter interactions with CDH3-eQTL, absent in normal stomach and parental cells. CDH3-eQTL deletion promotes CDH3/CDH1 reduced expression. These data provide evidence that loss of CDH1/E-cadherin expression alters the CDH3 locus chromatin conformation, allowing a CDH1 promoter interaction with a CDH3-eQTL, and promoting CDH3/P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.
Dados da publicação
- ISSN/ISSNe:
- 2079-7737, 2079-7737
- Tipo:
- Article
- Páginas:
- 803-
- Link para outro recurso:
- www.scopus.com
BIOLOGY-BASEL Multidisciplinary Digital Publishing Institute (MDPI)
Citações Recebidas na Scopus: 2
Documentos
- Não há documentos
Filiações
Keywords
- gastric cancer; cadherins switch; regulatory elements; 3D chromatin architecture; chromatin interactions; CDH1; CDH3
Financiamento
Proyectos asociados
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Citar a publicação
José CS,Pereira C,Ferreira M,Andr? A,Osório H,Gullo I,Carneiro F,Oliveira C. 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-Basel. 2023. 12. (6):p. 803-803. IF:4,200. (2).
