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Belinostat exerts anti-tumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma. (Mol Oncol, Apr 2017)

Kong LR1, Tan TZ1, Ong WR2, Bi C1, Huynh H2, Lee SC1,3,4, Chng WJ1,3,4, Eichhorn PJ1,3,5, Goh BC1,3,5,4.

Author information
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 National Cancer Centre, Singapore.
3 National University Cancer Institute, Singapore.
4 Department of Hematology-Oncology, National University Hospital, Singapore.
5 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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 (HDAC) inhibitor. Phosphoproteomic analysis of belinostat-treated SCC cells revealed significant downregulation of the MAPK pathway, along with 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 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 chemo-refractory SCC tumors.

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KEYWORDS: Lung squamous cell carcinoma; MAPK inhibition; histone deacetylase inhibitors; ubiquitin-proteasome system

PMID: 28397399