PT  - JOURNAL ARTICLE
AU  - Cristian Prieto-Garcia
AU  - Oliver Hartmann
AU  - Michaela Reissland
AU  - Thomas Fischer
AU  - Carina R. Maier
AU  - Mathias Rosenfeldt
AU  - Christina Schülein-Völk
AU  - Kevin Klann
AU  - Reinhard Kalb
AU  - Ivan Dikic
AU  - Christian Münch
AU  - Markus E. Diefenbacher
TI  - Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway
AID  - 10.1101/2020.09.10.291278
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.10.291278
4099  - http://biorxiv.org/content/early/2020/09/10/2020.09.10.291278.short
4100  - http://biorxiv.org/content/early/2020/09/10/2020.09.10.291278.full
AB  - Squamous cell carcinomas (SCC) frequently have a limited response to or develop resistance to platinum-based chemotherapy, and have an exceptionally high tumor mutational burden. As a consequence, overall survival is limited and novel therapeutic strategies are urgently required, especially in light of a rising incidences. SCC tumors express ΔNp63, a potent regulator of the Fanconi Anemia (FA) DNA-damage response pathway during chemotherapy, thereby directly contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 affects the FA DNA repair pathway during cisplatin treatment in SCC, thereby influencing therapy outcome. In an ATR-dependent fashion, USP28 is phosphorylated and activated to positively regulate the DNA damage response. Inhibition of USP28 reduces recombinational repair via an ΔNp63-Fanconi Anemia pathway axis, and weakens the ability of tumor cells to accurately repair DNA. Our study presents a novel mechanism by which tumor cells, and in particular ΔNp63 expressing SCC, can be targeted to overcome chemotherapy resistance.Significance Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ΔNp63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-ΔNp63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.Competing Interest StatementThe authors have declared no competing interest.