Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Abstract

The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

“…Thanks to the substantial advances in understanding the molecular basis of cancer initiation, progression, metastasis, and drug resistance, several promising molecular targets have been characterized for cancer drug discovery, including β-catenin ( Cui et al., 2018 ; Qi et al., 2020 ). Considering the critical role of β-catenin signaling in cancer development and progression, several targeting strategies have been developed to inhibit β-catenin, resulting in the identification of various types of β-catenin inhibitors ( Krishnamurthy and Kurzrock, 2018 ; Qin et al., 2018b ).…”

RBM10, a New Regulator of p53

“…On the other hand, in response to DNA damage signals, ATM phosphorylates MDM2 at serine 395, suppressing MDM2 activity toward p53 and consequently activating the latter [79]. Thus, this MDM2-p53 pathway is highly regulated via a variety of signaling pathways, as further discussed below and reviewed by others recently [80][81][82][83]. Furthermore, ATM/ATR-Chk2/Chk1 kinase cascades can lead to MDMX phosphorylation at S342, S367, and S402 in response to DNA damage [84][85][86][87].…”

Targeting ubiquitin signaling for cancer immunotherapy

“… 220 – 223 The most extensively explored DUB for drug development is USP7 with a large number of small molecule inhibitors being developed. 224 In addition to its well-known function in mediating deubiquitination and stabilization of MDM2, 222 USP7 stabilizes Foxp3 and a histone acetyl transferase, Tip60, thereby maintaining the function of Treg cells in the immune system. 165 , 225 Treatment of mice with different USP7 inhibitors impairs the immunosuppressive functions of Treg cells and promote antitumor immunity.…”

“…Small molecule inhibitors for several DUBs have also been developed, and some of them have been shown to inhibit tumor growth in animal models. [220][221][222][223] The most extensively explored DUB for drug development is USP7 with a large number of small molecule inhibitors being developed. 224 In addition to its wellknown function in mediating deubiquitination and stabilization of MDM2, 222 USP7 stabilizes Foxp3 and a histone acetyl transferase, Tip60, thereby maintaining the function of Treg cells in the immune system.…”