TY  - JOUR
A1  - Prieto-Garcia, Cristian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Braun, Fabian
A1  - Bozkurt, Süleyman
A1  - Pahor, Nikolett
A1  - Fuss, Carmina
A1  - Schirbel, Andreas
A1  - Schülein-Völk, Christina
A1  - Buchberger, Alexander
A1  - Calzado Canale, Marco A.
A1  - Rosenfeldt, Mathias
A1  - Dikic, Ivan
A1  - Münch, Christian
A1  - Diefenbacher, Markus E.
T1  - USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K
JF  - Molecular Oncology
N2  - Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a ‘premalignant’ state, and its inhibition synergizes with clinically established compounds used to target EGFR\(^{L858R}\)-, BRAF\(^{V600E}\)- or PI3K\(^{H1047R}\)-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.
KW  - buparlisib
KW  - c-MYC
KW  - gefitinib
KW  - lung cancer
KW  - USP28
KW  - vemurafenib
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312777
VL  - 16
IS  - 17
ER  - 
TY  - JOUR
A1  - Prieto-Garcia, Cristian
A1  - Tomašković, Ines
A1  - Shah, Varun Jayeshkumar
A1  - Dikic, Ivan
A1  - Diefenbacher, Markus
T1  - USP28: oncogene or tumor suppressor? a unifying paradigm for squamous cell carcinoma
JF  - Cells
N2  - 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.
KW  - USP28
KW  - SCC
KW  - USP25
KW  - FBXW7
KW  - Tp63
KW  - c-MYC
KW  - ΔNp63
KW  - p53
KW  - cancer
KW  - DUB inhibitor
KW  - squamous
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248409
SN  - 2073-4409
VL  - 10
IS  - 10
ER  -