USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis

Abstract

Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis.

Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis

“…In addition, the decreased PHF8 protein expression under USP7 depletion was not a result of reduced PHF8 mRNA, as quantitative reverse transcription PCR (qRT-PCR) measurements indicated that USP7 knockdown did not result in alterations in PHF8 mRNA level in MCF-7 cells and ubiquitination (25). In addition, reports also implicate USP7 in several pathological states, including neurodevelopmental and neurodegenerative disorders (26), inflammation (27), dilated cardiomyopathy (28), and various types of malignancies (29)(30)(31). However, the mechanistic insights into the role of USP7 in tumor development and progression remain to be investigated.…”

USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs

“…Early studies on USP7 inhibition have shown antitumor properties in multiple myeloma [21], in neuroblastoma [22] and in p53 wild-type and null isogenic cancer cells [23]. Thus, in this study we have evaluated in L-NET cell lines the effects of the pharmacological inhibition of the de-ubiquitinase enzyme USP7.…”

Therapeutic opportunities within the DNA damage response

“…These deubiquitylating/deubiquitinating enzymes (DUBs) of which ~100 are identifiable in the human genome, hydrolyse the isopeptide bond linking the C-terminal glycine of ubiquitin with a lysine side chain on the target protein or another ubiquitin molecule. Usp1, which deubiquitylates PCNA and FANCD2, and Usp7, which deubiquitylates Mdm2, TP53 and a range of proteins involved in BER, NER and DNA damage checkpoint signalling, have been at the forefront of drug discovery for this class of enzymes 65,66 . There are 37 DUBs reported to interact with DDR proteins (Supplementary information S17 (table)) of which 23 are predicted to be druggable and of which 2 had reported inhibitors.…”