3D Chromatin Architecture Re-Wiring at the CDH3/CDH1 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. and mRNA expression was obtained from 42 gastric tumours' RNA-seq data. CRISPR-Cas9 was used to knock out and a putative regulatory element. -depleted and parental cells were submitted to proteomics and enrichment GO terms analysis; ATAC-seq/4C-seq with a promoter viewpoint to assess chromatin accessibility and conformation; and RT-PCR/flow cytometry to assess /E-cadherin and /P-cadherin expression. In 42% of gastric tumours analysed, to switch was observed. knockout triggered /E-cadherin complete loss and /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 promoter interactions with -eQTL, absent in normal stomach and parental cells. -eQTL deletion promotes / reduced expression. These data provide evidence that loss of /E-cadherin expression alters the locus chromatin conformation, allowing a promoter interaction with a -eQTL, and promoting /P-cadherin expression. These data highlight a novel mechanism triggering E- to P-cadherin switch in gastric cancer.