Open AccessBelinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma
Author(s) -
Kong Li R.,
Tan Tuan Z.,
Ong Weijie R.,
Bi Chonglei,
Huynh Hung,
Lee Soo C.,
Chng Wee J.,
Eichhorn Pieter J. A.,
Goh Boon C.
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12064
Subject(s) - cancer research , mapk/erk pathway , downregulation and upregulation , histone deacetylase , bortezomib , cytotoxicity , proteasome , cisplatin , gene knockdown , mg132 , apoptosis , proteasome inhibitor , chemistry , biology , signal transduction , microbiology and biotechnology , histone , immunology , biochemistry , chemotherapy , in vitro , genetics , multiple myeloma , gene
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 FBXO 3 and FBXW 10, 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 si RNA knockdown of FBXO 3/ FBXW 10 . 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.