PMID- 24747969
OWN - NLM
STAT- MEDLINE
DCOM- 20150604
LR  - 20230614
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 13
DP  - 2015 Mar 26
TI  - MUC4 regulates cellular senescence in head and neck squamous cell carcinoma 
      through p16/Rb pathway.
PG  - 1698-708
LID - 10.1038/onc.2014.102 [doi]
AB  - 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 beta-galactosidase (SA-beta-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.
FAU - Macha, M A
AU  - Macha MA
AD  - Department of Biochemistry and Molecular Biology, Eppley Institute for Research 
      in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Rachagani, S
AU  - Rachagani S
AD  - Department of Biochemistry and Molecular Biology, Eppley Institute for Research 
      in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Pai, P
AU  - Pai P
AD  - Department of Biochemistry and Molecular Biology, Eppley Institute for Research 
      in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Gupta, S
AU  - Gupta S
AD  - Department of Biochemistry and Molecular Biology, Eppley Institute for Research 
      in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Lydiatt, W M
AU  - Lydiatt WM
AD  - Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Smith, R B
AU  - Smith RB
AD  - Department of Otolaryngology, University of Nebraska Medical Center, Omaha, NE, 
      USA.
FAU - Johansson, S L
AU  - Johansson SL
AD  - Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
FAU - Lele, S M
AU  - Lele SM
AD  - Department of Pathology, University of Nebraska Medical Center, Omaha, NE, USA.
FAU - Kakar, S S
AU  - Kakar SS
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      KY, USA.
FAU - Farghaly, H
AU  - Farghaly H
AD  - Department of Physiology and Biophysics, University of Louisville, Louisville, 
      KY, USA
FAU - Lee, J H
AU  - Lee JH
AD  - Sanford ENT-Head and Neck Surgery, Sanford Cancer Research Center, Sioux Falls, 
      SD, USA.
FAU - Meza, J
AU  - Meza J
AD  - Department of Biostatistics, College of Public Health, University of Nebraska 
      Medical Center, Omaha, NE, USA.
FAU - Ganti, A K
AU  - Ganti AK
AD  - Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and 
      University of Nebraska Medical Center, Omaha, NE, USA.
FAU - Jain, M
AU  - Jain M
AD  - 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.
FAU - Batra, S K
AU  - Batra SK
AD  - 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.
LA  - eng
GR  - U54 CA163120/CA/NCI NIH HHS/United States
GR  - U01 CA111294/CA/NCI NIH HHS/United States
GR  - P50 CA 127297/CA/NCI NIH HHS/United States
GR  - P50 CA127297/CA/NCI NIH HHS/United States
GR  - R21 CA156037/CA/NCI NIH HHS/United States
GR  - R01 CA133774/CA/NCI NIH HHS/United States
GR  - P20 GM103480/GM/NIGMS NIH HHS/United States
GR  - UO1 CA111294/CA/NCI NIH HHS/United States
GR  - P20 RR021937/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140421
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (CDKN2A protein, human)
RN  - 0 (Cyclin E)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (MUC4 protein, human)
RN  - 0 (Mucin-4)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Retinoblastoma Protein)
SB  - IM
EIN - Oncogene. 2015 May 21;34(21):2814. Farghaly, H [added]. PMID: 25994150
MH  - Animals
MH  - Carcinoma, Squamous Cell/*pathology
MH  - Cell Cycle Checkpoints
MH  - Cell Line, Tumor
MH  - Cell Movement
MH  - Cell Proliferation
MH  - *Cellular Senescence
MH  - Chromatin Assembly and Disassembly
MH  - Cyclin E/analysis
MH  - Cyclin-Dependent Kinase Inhibitor p16
MH  - Head and Neck Neoplasms/*pathology
MH  - Humans
MH  - Mice
MH  - Mucin-4/analysis/*physiology
MH  - Neoplasm Invasiveness
MH  - Neoplasm Proteins/*physiology
MH  - Retinoblastoma Protein/*physiology
MH  - Squamous Cell Carcinoma of Head and Neck
PMC - PMC4205229
MID - NIHMS591176
EDAT- 2014/04/22 06:00
MHDA- 2015/06/05 06:00
PMCR- 2016/03/26
CRDT- 2014/04/22 06:00
PHST- 2014/01/24 00:00 [received]
PHST- 2014/03/10 00:00 [revised]
PHST- 2014/03/17 00:00 [accepted]
PHST- 2014/04/22 06:00 [entrez]
PHST- 2014/04/22 06:00 [pubmed]
PHST- 2015/06/05 06:00 [medline]
PHST- 2016/03/26 00:00 [pmc-release]
AID - onc2014102 [pii]
AID - 10.1038/onc.2014.102 [doi]
PST - ppublish
SO  - Oncogene. 2015 Mar 26;34(13):1698-708. doi: 10.1038/onc.2014.102. Epub 2014 Apr 
      21.