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

Evgenia Gubanova, Brandee Brown, Sergei V. Ivanov, Thomas Helleday, Gordon Mills, Wendell G. Yarbroug, Natalia Issaeva

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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. Animportant 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 HPVpositive 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.

Original languageEnglish (US)
Pages (from-to)1257-1267
Number of pages11
JournalClinical Cancer Research
Volume18
Issue number5
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Down-Regulation
Survival
Ionizing Radiation
DNA Damage
Neoplasms
Radiation Tolerance
Carcinoma, squamous cell of head and neck
Genitalia
Papillomavirus Infections
Tumor Cell Line
Methylation
Small Interfering RNA
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. / Gubanova, Evgenia; Brown, Brandee; Ivanov, Sergei V.; Helleday, Thomas; Mills, Gordon; Yarbroug, Wendell G.; Issaeva, Natalia.

In: Clinical Cancer Research, Vol. 18, No. 5, 01.03.2012, p. 1257-1267.

Research output: Contribution to journalArticle

Gubanova, Evgenia ; Brown, Brandee ; Ivanov, Sergei V. ; Helleday, Thomas ; Mills, Gordon ; Yarbroug, Wendell G. ; Issaeva, Natalia. / Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 5. pp. 1257-1267.
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AU - Ivanov, Sergei V.

AU - Helleday, Thomas

AU - Mills, Gordon

AU - Yarbroug, Wendell G.

AU - Issaeva, Natalia

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AB - 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. Animportant 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 HPVpositive 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.

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