Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival.

Gubanova E, Brown B, Ivanov SV, Helleday T, Mills GB, Yarbrough WG, Issaeva N
Clin Cancer Res. 2012 18 (5): 1257-67

PMID: 22247495 · PMCID: PMC4010255 · DOI:10.1158/1078-0432.CCR-11-2058

PURPOSE - Human papillomavirus (HPV) is linked with a subset of head and neck squamous cell carcinomas (HNSCC). HPV-positive HNSCCs show a better prognosis than HPV-negative HNSCCs, which may be explained by sensitivity of the HPV-positive HNSCCs to ionizing radiation (IR). Although the molecular mechanism behind sensitivity to IR in HPV-positive HNSCCs is unresolved, DNA damage response (DDR) might be a significant determinant of IR sensitivity. An important player in the DDR, SMG-1 (suppressor with morphogenetic effect on genitalia), is a potential tumor suppressor and may therefore be deregulated in cancer. No studies have yet been conducted linking defects in SMG-1 expression with cancer. We investigated whether deregulation of SMG-1 could be responsible for defects in the DDR in oropharyngeal HNSCC.

EXPERIMENTAL DESIGN - Expression and promoter methylation status of SMG-1 were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an E6/E7 expression construct. SMG-1 short hairpin RNAs were expressed in HPV-negative cells to estimate survival upon IR.

RESULTS - Forced E6/E7 expression in HPV-negative cells resulted in SMG-1 promoter hypermethylation and decreased SMG-1 expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express SMG-1 at lower levels than HPV-negative SCCs. Depletion of SMG-1 in HPV-negative HNSCC cells resulted in increased radiation sensitivity, whereas SMG-1 overexpression protected HPV-positive tumor cells from irradiation.

CONCLUSIONS - Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished SMG-1 expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs.

MeSH Terms (25)

Adult Aged Apoptosis Ataxia Telangiectasia Mutated Proteins Carcinoma, Squamous Cell Cell Cycle Proteins Cell Line DNA-Binding Proteins DNA Methylation Down-Regulation Female Gene Expression Regulation, Neoplastic Head and Neck Neoplasms Human papillomavirus 16 Humans Male Middle Aged Oncogene Proteins, Viral Papillomavirus E7 Proteins Phosphatidylinositol 3-Kinases Promoter Regions, Genetic Protein-Serine-Threonine Kinases Radiation Tolerance Repressor Proteins Tumor Suppressor Proteins

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