Abstract
Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate is less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization of the oncoproteins c-MYC, c-JUN, and Δp63. Here, we show that genetic inactivation of Usp28-induced regression of established murine LSCC lung tumours. We developed a small molecule that inhibits USP28 activity in the low nanomole range. While displaying cross-reactivity against the closest homologue USP25, this inhibitor showed a high degree of selectivity over other deubiquitinases. USP28 inhibitor treatment resulted in a dramatic decrease in c-MYC, c-JUN, and Δp63 proteins levels and consequently induced substantial regression of autochthonous murine LSCC tumours and human LSCC xenografts, thereby phenocopying the effect observed by genetic deletion. Thus, USP28 may represent a promising therapeutic target for the treatment of squamous cell lung carcinoma.
Highlights
Lung cancer is the leading cause of cancer death worldwide
Here, we describe the characterisation of a novel ubiquitin specific protease 28 53 (USP28) inhibitory compound (USP28i) and the genetic as well as chemical validation of USP28 as a promising therapeutic target for Lung squamous cell carcinoma (LSCC) tumours
P63 and c-JUN, critical factors in squamous cell identity and tumour maintenance, respectively, showed higher protein levels in LSCC compared to lung adenocarcinoma (LADC) tumours (Figure 1C, 1D)
Summary
Lung cancer is the leading cause of cancer death worldwide. Based on histological criteria lung cancer can be subdivided into non-small cell lung cancer (NSCLC) and the rarer small cell lung cancer. The Fbxw[7] protein product F-box/WD repeat-containing protein 7 (FBXW7) is the substrate recognition component of an SCF-type ubiquitin ligase, which targets several well-known oncoproteins, including c-MYC, NOTCH, and c-JUN, for degradation (Davis et al, 2014). These oncoproteins accumulate in the absence of FBW7 function, and genetic analyses of human LSCC samples revealed common genomic alterations in Fbxw[7] (Cancer Genome Atlas Research, 2012; Kan et al, 2010). Absence or inhibition of USP28 resulted in a dramatic decrease in the protein levels of c-MYC, c-JUN and p63, providing a potential mechanism of action for USP28i. USP28 inhibition should be a strong candidate for clinical evaluation, given the paucity of currently available therapy options for LSCC patients. 110
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