Inhibition of USP28 overcomes Cisplatin-Resistance of Squamous Tumors by Suppression of the Fanconi Anemia Pathway

Abstract

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.SignificanceLimited 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.

Ubiquitin‐specific protease 28 deubiquitinates TCF7L2 to govern the action of the Wnt signaling pathway in hepatic carcinoma

“…30,31 In addition, the sensitivity of SCC to chemotherapy can be improved by inhibiting the USP28-DNp63-DDR axis. 32 Here we show that this deubiquitinase is also important in liver cancer cells with constitutively active Wnt signaling. Our results show that USP28 contributes to the activity of the Wnt signaling pathway through stabilizing TCF7L2 (Figure 7), at least partially, as it also regulates other members of the TCF/LEF family transcription factors (Figure 2A) as well as Forkhead box protein M1 (FOXM1), another transcription factor involved in Wnt signaling.…”

“…It was shown that the intestinal tumorigenesis induced by the inactivation of Apc was hindered in Usp28 ‐deficient mice, 14 triple‐ negative breast cancer cells depend on USP28 for proliferation and survival due to its role in maintaining the stability of RecQ family helicases, 29 and SCC cells require USP28 for proliferation due to its function in maintaining the stability of ΔNp63 30,31 . In addition, the sensitivity of SCC to chemotherapy can be improved by inhibiting the USP28‐DNp63‐DDR axis 32 . Here we show that this deubiquitinase is also important in liver cancer cells with constitutively active Wnt signaling.…”

USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K

“…Overall, USP28 functions as a proto-oncogene and contributes to establishing the hallmarks of cancer in cells undergoing oncogenic transformation, at least in lung [21,[50][51][52]. Here, USP28 is expressed in the stem cell niche and elevated abundance detected in 'cells of origin'.…”