title: MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway.
abstract: The limited effectiveness of therapy for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) or recurrent disease is a reflection of an incomplete understanding of the molecular basis of HNSCC pathogenesis. MUC4, a high molecular weight glycoprotein, is differentially overexpressed in many human cancers and implicated in cancer progression and resistance to several chemotherapies. However, its clinical relevance and the molecular mechanisms through which it mediates HNSCC progression are not well understood. This study revealed a significant upregulation of MUC4 in 78% (68/87) of HNSCC tissues compared with 10% positivity (1/10) in benign samples (P=0.006, odds ratio (95% confidence interval)=10.74 (2.0-57.56). MUC4 knockdown (KD) in SCC1 and SCC10B HNSCC cell lines resulted in significant inhibition of growth in vitro and in vivo, increased senescence as indicated by an increase in the number of flat, enlarged and senescence-associated β-galactosidase (SA-β-Gal)-positive cells. Decreased cellular proliferation was associated with G0/G1 cell cycle arrest and decrease expression of cell cycle regulatory proteins like cyclin E, cyclin D1 and decrease in BrdU incorporation. Mechanistic studies revealed upregulation of p16, pRb dephosphorylation and its interaction with histone deacetylase 1/2. This resulted in decreased histone acetylation (H3K9) at cyclin E promoter leading to its downregulation. Orthotopic implantation of MUC4 KD SCC1 cells into the floor of the mouth in nude mice resulted in the formation of significantly smaller tumors (170±18.30 mg) compared to those (375±17.29 mg) formed by control cells (P=0.00007). In conclusion, our findings showed that MUC4 overexpression has a critical role by regulating proliferation and cellular senescence of HNSCC cells. Downregulation of MUC4 may be a promising therapeutic approach for treating HNSCC patients.
authors.affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Macha
authors.affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rachagani
authors.affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: P
authors.initials: P
authors.lastname: Pai
authors.affiliation: Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Lydiatt
authors.affiliation: Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Johansson
authors.affiliation: Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lele
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Kakar
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, KY, USA
authors.forename: H
authors.initials: H
authors.lastname: Farghaly
authors.affiliation: Sanford ENT-Head and Neck Surgery, Sanford Cancer Research Center, Sioux Falls, SD, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meza
authors.affiliation: Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Ganti
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA [2] Buffett Cancer Center, Omaha, NE, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jain
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA [2] Buffett Cancer Center, Omaha, NE, USA [3] Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D019927:Cyclin E / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D055264:Mucin-4 / Q000032:analysis / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C000614131:CDKN2A protein, human; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; C524658:MUC4 protein, human; D055264:Mucin-4; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein
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