Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms

Abstract

Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4⁺ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.

Keywords: DUBs; USP22; cancer; deubiquitination; immune evasion; ubiquitylation.

Figure 1

E1, E2, and E3 ubiquitination and DUB deubiquitination (ubiquitin connects to target proteins via E1, E2, and E3. DUB removes ubiquitin from substrates and recovers ubiquitin molecules).

Figure 2

USP22-mediated immune evasion (USP22 can directly regulate PD-L1 stability through deubiquitination; on the other hand, USP22 regulates PD-L1 protein levels through the USP22-CSN5-PD-L1 axis. USP22 expression inhibits T-cell infiltration into tumors. The PD-1/PD-L1 axis contributes to tumor cell escape by inhibiting T-cell activation).

Figure 3

USP22-mediated tumor stemness in a hypoxic microenvironment (USP22 upregulates stemness gene expression via Wnt/β-catenin, HIF-1α, and BMI1 pathways).

Figure 4

USP22 mediates tumor resistance mechanisms to enzalutamide, cisplatin, and 5-fluorouracil (USP22 can make cancer cells resistant to 5-FU through SIRT1 and Wnt/β-catenin signaling. USP22 mediates tumor resistance to cisplatin by acting on ALDH1A3, PALB2, H2A, H2B, and SIRT1. Binding of USP22 to AR/AR-V7 prevents AR/AR-V7 protein degradation and enhances tumor resistance to enzalutamide).