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.

Differential Role of the RasGEFs Sos1 and Sos2 in Mouse Skin Homeostasis and Carcinogenesis

“…In this regard, it was reported that ERK activation occurs at the transition from papilloma to SCC (50). In addition, Sos upregulation leads to cisplatin resistance in SCC cells through mitogenactivated protein kinase (MAPK)/ERK activation (51), and belinostat blocks Sosmediated MAPK activation, exerting an antitumor effect in SCC (52). It has also been reported that the absence of Rac activators such as Tiam1 or Vav2/3 has a potential therapeutic effect in DMBA/TPA-induced skin tumors (53,54).…”

RETRACTED ARTICLE: Belinostat suppresses cell proliferation by inactivating Wnt/β-catenin pathway and promotes apoptosis through regulating PKC pathway in breast cancer

“…Emerging evidence confirmed that Belinostat showed significant regulatory impacts on cell survival and metastasis [14]. As Kong et al found that Belinostat emerged the anti-tumour cytotoxicity induced cells apoptosis by repression of MAPK pathway in lung squamous cell carcinoma [15]. In addition, Wang et al testified that Belinostat could induce pancreatic cancer cells apoptosis and prohibit growth by activation of TAK1-AMPK signal pathway [16].…”

From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs

“…Finally, the last step in proteostasis involves the decomposition of proteins, performed either by proteasomal degradation or autophagy, both of which play key roles in aging and can be regulated by HDACs (Scognamiglio et al , ; Trüe & Matthias, ; Milota et al , ; Cellerino & Ori, ; Kong et al , ). For instance, HDAC inhibitor treatments in several cancer cell lines activate the ubiquitin–proteasome pathway, leading to increased protein degradation (Scognamiglio et al , ; Hakami et al , ; Kong et al , ). HDAC inhibitors also induce autophagy (Hrzenjak et al , ; Liu et al , ), as does genetic knockdown of HDAC1 (Oh et al , ).…”