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.

A risk signature of ubiquitin-specific protease family predict the prognosis and therapy of kidney cancer patients

“…Therefore, novel treatments for metastatic KIRC still need to develop and explore. Studies have indicated that USPs are pivotal for cancer progression, and several USPs have been utilized as targets to develop inhibitors for cancer prevention [ 18 , 24 , 25 ]. ML364 is a small molecule inhibitor of the deubiquitinase USP2, which could degrade CCND1 and prevent cancer cell cycle progression in colorectal cancer [ 26 ]; USP7 could induce apoptosis in multiple myeloma cells resistant to conventional and bortezomib therapies [ 27 ]; Developing the medicines based on the USPs are considered as a potential new treatment for cancer.…”

Targeted therapy based on ubiquitin-specific proteases, signalling pathways and E3 ligases in non-small-cell lung cancer

“…USP22 is highly expressed in various tumours such as lung ( 72 ), colorectal ( 73 ) and gastric cancers ( 74 ), and is involved in DNA transcription, malignant transformation of cells and cell cycle progression ( 75 ).…”

Exosomal long non-coding RNAs: novel molecules in gastrointestinal cancers’ progression and diagnosis

“…The programmed death receptor 1 (PD-1) has been reported in several studies to mediate resistance to immune attack in cancer ( 207 – 209 ). The programmed death ligand 1 (PD-L1)/ubiquitin-specific protease 22 (USP22) axis has been found to control tumor immune escape ( 210 – 212 ). USP22 is considered to be an oncogene and can enhance the stability of substrate proteins through the inhibition of proteasomal degradation ( 213 ).…”