title: Belinostat exerts antitumor cytotoxicity through the ubiquitin-proteasome pathway in lung squamous cell carcinoma.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Li R
authors.initials: LR
authors.lastname: Kong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Tuan Z
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: National Cancer Centre, Singapore.
authors.forename: Weijie R
authors.initials: WR
authors.lastname: Ong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Chonglei
authors.initials: C
authors.lastname: Bi
authors.affiliation: National Cancer Centre, Singapore.
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.|Department of Hematology-Oncology, National University Hospital, Singapore.
authors.forename: Soo C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.|Department of Hematology-Oncology, National University Hospital, Singapore.
authors.forename: Wee J
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Pieter J A
authors.initials: PJA
authors.lastname: Eichhorn
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|National University Cancer Institute, Singapore.|Department of Hematology-Oncology, National University Hospital, Singapore.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Boon C
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D013449:Sulfonamides; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C487081:belinostat
keywords: MAPK inhibition; histone deacetylase inhibitors; lung squamous cell carcinoma; ubiquitin-proteasome system