title: POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in head and neck cancer.
abstract: HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sharpe
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL.
authors.forename: Katy S
authors.initials: KS
authors.lastname: Orr
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL.
authors.forename: Michael
authors.initials: M
authors.lastname: Moran
authors.affiliation: Pathology Department, Ninewells Hospital and Medical School, Dundee, DD1 9SY.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: White
authors.affiliation: The Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL and The Belfast Trust, Belfast City Hospital, Lisburn Road, Belfast.
authors.forename: Stephen
authors.initials: S
authors.lastname: McQuaid
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL.
authors.forename: Terence R
authors.initials: TR
authors.lastname: Lappin
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL. The Northern Ireland Molecular Pathology Laboratory, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL and The Belfast Trust, Belfast City Hospital, Lisburn Road, Belfast.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: James
mesh_terms: D001665:Binding Sites; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D034622:RNA Interference; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C489493:HOXD11 protein, human; D018398:Homeodomain Proteins; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D014157:Transcription Factors; C072064:HOXD10 protein, human