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 G 0/G 1 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.

Original languageEnglish (US)
Pages (from-to)1698-1708
Number of pages11
JournalOncogene
Volume34
Issue number13
DOIs
StatePublished - Mar 26 2015

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Cell Aging
Cyclin E
Histone Deacetylase 2
Up-Regulation
Down-Regulation
Histone Deacetylase 1
Galactosidases
Mouth Floor
Neoplasms
Gastrin-Secreting Cells
Cell Cycle Proteins
Cyclin D1
Bromodeoxyuridine
Acetylation
Cell Cycle Checkpoints
Carcinoma, squamous cell of head and neck
Nude Mice
Histones
Glycoproteins
Molecular Weight

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. / Macha, Muzafar A; Rachagani, Satyanarayana; Pai, P.; Gupta, S.; Lydiatt, W. M.; Smith, R. B.; Johansson, S. L.; Lele, Subodh M; Kakar, S. S.; Lee, J. H.; Meza, Jane L; Ganti, Apar Kishor P; Jain, Maneesh; Batra, Surinder Kumar.

In: Oncogene, Vol. 34, No. 13, 26.03.2015, p. 1698-1708.

Research output: Contribution to journalArticle

Macha, Muzafar A ; Rachagani, Satyanarayana ; Pai, P. ; Gupta, S. ; Lydiatt, W. M. ; Smith, R. B. ; Johansson, S. L. ; Lele, Subodh M ; Kakar, S. S. ; Lee, J. H. ; Meza, Jane L ; Ganti, Apar Kishor P ; Jain, Maneesh ; Batra, Surinder Kumar. / MUC4 regulates cellular senescence in head and neck squamous cell carcinoma through p16/Rb pathway. In: Oncogene. 2015 ; Vol. 34, No. 13. pp. 1698-1708.
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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 G 0/G 1 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.",
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AU - Rachagani, Satyanarayana

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AU - Gupta, S.

AU - Lydiatt, W. M.

AU - Smith, R. B.

AU - Johansson, S. L.

AU - Lele, Subodh M

AU - Kakar, S. S.

AU - Lee, J. H.

AU - Meza, Jane L

AU - Ganti, Apar Kishor P

AU - Jain, Maneesh

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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 β-galactosidase (SA-β-Gal)-positive cells. Decreased cellular proliferation was associated with G 0/G 1 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.

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