title: Alterations in RD(INK4/ARF) -mediated en bloc regulation of the INK4-ARF locus in human squamous cell carcinoma of the head and neck.
abstract: The presence of RD(INK4/ARF) (RD) enhancer in the INK4-ARF locus provides a novel mechanism to simultaneously increase the transcription of p15(INK4b) (p15), p14ARF (p14), and p16(INK4a) (p16). While such upregulation can be repressed through interactions between RD and oncoproteins CDC6 and BMI1, little is known about the involvement of RD in cancer. In this study we investigated RD deletions in 30 squamous cell carcinoma of the head and neck (SCCHN) and the patient-matched High At-Risk Mucosa specimens (HARM, "phenotypically normal" tissues neighboring SCCHN foci but beyond the surgical resection margin). RD was deleted (homozygously/heterozygously) in SCCHN and HARM at the incidence of 36.7% (11/30) and 13.3% (4/30), respectively. In comparison, no RD deletion was detected in 26 oral buccal brush biopsy specimens from healthy donors. Both p16 and p14 were lowly expressed in SCCHN and HARM, and their mRNA expression levels were positively associated with each other (P < 0.01). Moreover, BMI1 was highly expressed in both SCCHN and HARM, and BMI1 overexpression was associated with p16 downregulation in SCCHN (P < 0.05). These results indicate that RD deletion and BMI1 overexpression frequently occur in the early stage of oral carcinogenesis and BMI1 overexpression may downregulate the transcription of p16 and p14 through interfering with RD.
authors.affiliation: Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio.
authors.forename: Ming J
authors.initials: MJ
authors.lastname: Poi
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Knobloch
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.
authors.forename: Marta T
authors.initials: MT
authors.lastname: Sears
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.
authors.forename: Blake M
authors.initials: BM
authors.lastname: Warner
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.
authors.forename: Lana K
authors.initials: LK
authors.lastname: Uhrig
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Weghorst
authors.affiliation: Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Junan
authors.initials: J
authors.lastname: Li
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
chemical_list: C069077:BMI1 protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D063150:Polycomb Repressive Complex 1
keywords: BMI1; RD enhancer; en bloc regulation; genetic deletion; the INK4-ARF locus