Please use this identifier to cite or link to this item: https://doi.org/10.1002/1878-0261.12064
Title: Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma
Authors: Kong, L.R 
Tan, T.Z 
Ong, W.R
Bi, C
Huynh, H 
Lee, S.C 
Chng, W.J 
Eichhorn, P.J.A 
Goh, B.C 
Keywords: B Raf kinase
belinostat
beta actin
caspase 3
cisplatin
F box protein
f box protein 3
f box protein W10
histone deacetylase 1
histone deacetylase 2
histone deacetylase 3
histone deacetylase 4
histone deacetylase 5
mitogen activated protein kinase
mitogen activated protein kinase 1
mitogen activated protein kinase 3
mitogen activated protein kinase kinase 1
mitogen activated protein kinase kinase 2
mitogen activated protein kinase p38
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
proteasome
protein c jun
protein kinase B
sirtuin 1
SOS protein
STAT2 protein
STAT3 protein
STAT5 protein
STAT6 protein
ubiquitin
unclassified drug
antineoplastic agent
belinostat
hydroxamic acid
proteasome
sulfonamide
tumor protein
ubiquitin
animal cell
animal experiment
animal model
animal tissue
apoptosis
Article
cancer inhibition
cancer resistance
cancer size
cell proliferation
cell viability
chemosensitization
combination drug therapy
concentration response
controlled study
cytotoxicity
down regulation
drug potentiation
enzyme activation
enzyme degradation
enzyme phosphorylation
female
gene expression
histone acetylation
human
human cell
IC50
in vivo study
lung cancer cell line
mouse
nonhuman
nucleotide sequence
phosphoproteomics
priority journal
RNA interference
signal transduction
squamous cell carcinoma cell line
squamous cell lung carcinoma
transcription regulation
treatment duration
upregulation
drug effects
lung tumor
MAPK signaling
metabolism
pathology
squamous cell carcinoma
tumor cell line
Antineoplastic Agents
Carcinoma, Squamous Cell
Cell Line, Tumor
Humans
Hydroxamic Acids
Lung Neoplasms
MAP Kinase Signaling System
Neoplasm Proteins
Proteasome Endopeptidase Complex
Sulfonamides
Ubiquitin
Issue Date: Jul-2017
Publisher: Wiley Blackwell
Citation: Kong, L.R, Tan, T.Z, Ong, W.R, Bi, C, Huynh, H, Lee, S.C, Chng, W.J, Eichhorn, P.J.A, Goh, B.C (2017-07). Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma. Molecular Oncology 11 (8) : 965-980. ScholarBank@NUS Repository. https://doi.org/10.1002/1878-0261.12064
Abstract: There have been advances in personalized therapy directed by molecular profiles in lung adenocarcinoma, but not in lung squamous cell carcinoma (SCC). The lack of actionable driver oncogenes in SCC has restricted the use of small-molecule inhibitors. Here, we show that SCC cell lines displayed differential sensitivities to belinostat, a pan-histone deacetylase inhibitor. Phosphoproteomic analysis of belinostat-treated SCC cells revealed significant downregulation of the MAPK pathway, along with the induction of apoptosis. In cisplatin-resistant cells that demonstrated aberrant MAPK activation, combined treatment with belinostat significantly inhibited cisplatin-induced ERK phosphorylation and exhibited strong synergistic cytotoxicity. Furthermore, belinostat transcriptionally upregulated the F-box proteins FBXO3 and FBXW10, which directly targeted son of sevenless (SOS), an upstream regulator of the MAPK pathway, for proteasome-mediated degradation. Supporting this, suppression of SOS/ERK pathway by belinostat could be abrogated by inhibiting proteasomal activity either with bortezomib or with siRNA knockdown of FBXO3/FBXW10. Taken together, these preclinical data offer a novel understanding of the epigenetic mechanism by which belinostat exerts its cytotoxicity and supports the combination with cisplatin in clinical settings for chemorefractory SCC tumors. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
Source Title: Molecular Oncology
URI: https://scholarbank.nus.edu.sg/handle/10635/173836
ISSN: 15747891
DOI: 10.1002/1878-0261.12064
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