期刊
ONCOGENE
卷 35, 期 25, 页码 3293-3302出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.390
关键词
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资金
- NIH/NIEHS [ES016936, ES024373]
- American Cancer Society (ACS) [RSG-13-078-01]
- University of Chicago Cancer Research Center [P30 CA014599]
- CTSA [UL1 TR000430]
- University of Chicago Friends of Dermatology Endowment Fund
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-beta (TGF-beta) pathway. Adding XPC or DDB1, or inhibiting the TGF-beta 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 sunassociated 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.
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