Abstract
Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
Highlights
Academic Editors: Fuad Iraqi and Protein Stability and Cancer Group, Department of Biochemistry and Molecular Biology, University of Würzburg, 97074 Würzburg, Germany
The balance between the expression and genetic status of Ubiquitin-specific peptidase 28 (USP28) substrates and regulators could determine the potential role of USP28 as an oncoprotein or tumor suppressor
In Squamous Cell Carcinoma (SCC) tumors, Usp28 can clearly be considered an oncogene because most tumors suffer from functional p53 alterations
Summary
Ubiquitination is one of the most relevant posttranslational modifications and regulates critical cellular processes, including protein degradation, cell cycle progression, autophagy, transcription or DNA repair. As reported for other DUBs [15,16], one cannot exclude the possibility that USP28 deubiquitinates itself, thereby avoiding proteasomal degradation and, in consequence, regulating its own stability Supporting this hypothesis, recent publications observed reduced USP28 protein levels upon pharmacological inhibition [17]. Nates FBXW7 itself upon autocatalytic ubiquitination (Figure 2B) [34] This dual regulation of USP28 and FBXW7 allows for control of the protein abundance of common substrates, such as c-MYC and NOTCH1. USP28 was originally identified as a protein involved in DNA damage response (DDR), interacting and stabilizing the double-strand break repair protein 53BP1 [10] This interaction results in the phosphorylation of USP28 on serine 67 and 714 upon exposure to ionizing radiation in an ATM-dependent manner [10,37]. SCC requires high levels of the axis USP28-∆Np63 to maintain the malignant phenotype and its pharmacologic inhibition dramatically reduces the number of SCC tumors in lung cancer mouse models [17]
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