title: TGF-β signaling links E-cadherin loss to suppression of nucleotide excision repair.
abstract: E-cadherin is a cell adhesion molecule best known for its function in suppressing tumor progression and metastasis. Here we show that E-cadherin promotes nucleotide excision repair through positively regulating the expression of xeroderma pigmentosum complementation group C (XPC) and DNA damage-binding protein 1 (DDB1). Loss of E-cadherin activates the E2F4 and p130/107 transcription repressor complexes to suppress the transcription of both XPC and DDB1 through activating the transforming growth factor-β (TGF-β) pathway. Adding XPC or DDB1, or inhibiting the TGF-β pathway, increases the repair of ultraviolet (UV)-induced DNA damage in E-cadherin-inhibited cells. In the mouse skin and skin tumors, UVB radiation downregulates E-cadherin. In sun-associated premalignant and malignant skin neoplasia, E-cadherin is downregulated in association with reduced XPC and DDB1 levels. These findings demonstrate a crucial role of E-cadherin in efficient DNA repair of UV-induced DNA damage, identify a new link between epithelial adhesion and DNA repair and suggest a mechanistic link of early E-cadherin loss in tumor initiation.
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Radiation Oncology and Cell Biology, New York University School of Medicine, New York, NY, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
authors.forename: Y Y
authors.initials: YY
authors.lastname: He
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008812:Mice, Hairless; D008856:Microscopy, Fluorescence; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D015820:Cadherins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D016212:Transforming Growth Factor beta; C086984:XPC protein, human