Regulation of excision repair cross-complementation group 1 by Snail contributes to cisplatin resistance in head and neck cancer.
OBJECTIVE
We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC).


METHODS
The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy.


RESULTS
The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis.


CONCLUSIONS
Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells.
Hsu
Dennis Shin-Shian
DS
Institue of Biochemistry, National Chung-Hsing University, Taichung, Taiwan.
Lan
Hsin-Yi
HY
Huang
Chi-Hung
CH
Tai
Shyh-Kuan
SK
Chang
Shyue-Yih
SY
Tsai
Tung-Lung
TL
Chang
Cheng-Chi
CC
Tzeng
Cheng-Hwai
CH
Wu
Kou-Juey
KJ
Kao
Jung-Yie
JY
Yang
Muh-Hwa
MH
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D046228:Microarray Analysis; D000071250:Snail Family Transcription Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin