TY  - JOUR
A1  - Pietro-Garcia, Christian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Fischer, Thomas
A1  - Maier, Carina R.
A1  - Rosenfeldt, Mathias
A1  - Schülein-Völk, Christina
A1  - Klann, Kevin
A1  - Kalb, Reinhard
A1  - Dikic, Ivan
A1  - Münch, Christian
A1  - Diefenbacher, Markus E.
T1  - Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway
T2  - Cell Death and Differentiation
N2  - Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.
KW  - USP28
KW  - Cisplatin
KW  - squamous tumors
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/27301
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-273014
SN  - 1476-5403
VL  - 29
IS  - 3
ER  -