3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 Loci Contributes to E-Cadherin to P-Cadherin Expression Switch in Gastric Cancer

• Type: Article in International Scientific Journal
• Date: 2023

Authors

São José, C (Author) Other; Pereira, C (Author) Other; Ferreira, M (Author) Other; André, A (Author) Other; Osório, H (Author) Other; Gullo, I (Author) Other; Carneiro F (Author) FMUP; Oliveira, C (Author) Other

Journal

Title: BIOLOGY-BASEL

Vol. 12

Final page: 803

Publisher: MDPI

Indexing

Scopus - 0 Citations

Other information

Authenticus ID: P-00Y-FGW

DOI: 10.3390/biology12060803

Abstract (EN): <jats:p>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.</jats:p>

Language: English

Type (Professor's evaluation): Scientific