Roles of ubiquitination in the crosstalk between tumors and the tumor microenvironment (Review)

Abstract

The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post-translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation-mediated tumor formation, and the function of cancer-associated fibroblasts and infiltrating immune cells (tumor-associated macrophages, T-cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.

A Novel Scoring Model of Deubiquitination Patterns Predicts Prognosis and Immunotherapeutic Response in Hepatocellular Carcinoma

“…Dysregulation of deubiquitination is associated with poor prognosis in HCC [19] . Identifying relevant prognostic signatures and formulating immunotherapeutic approaches for HCC may be aided by a deeper comprehension of the roles of various deubiquitination patterns and the characterization of TME infiltration [ 44 , 45 ].…”

The Role of Myeloid-Derived Suppressor Cells in the Treatment of Pancreatic Cancer

“…Crosstalk with MDSCs may also lead to reduced expression of macrophage MHC II, which in turn reduces the antigen-presenting capacity of macrophages, further causing immunosuppression. 62 , 63 Crosstalk between MDSCs and dendritic cell (DC) also results in impaired antigen uptake, presentation, and migration by DC, which ultimately skews DC toward an anti-inflammatory component, leading to decreased interferonγ production by T cells. 64 The tumor-promoting activity of tumor-associated neutrophils (TANs) is closely associated with PMN-MDSCs, and crosstalk between them would polarize neutrophils in the tumor microenvironment toward an N2 type biased immunosuppressive effect.…”

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

“…No other deubiquitinase inhibitors have been approved for clinical studies since then. Also, the discovered deubiquitinase inhibitors related to tumor treatment are mainly concentrated in the USP family, and the relationship between the inhibitors of non-USP family members and the treatment of malignant tumors needs to be further studied ( Zhang et al, 2022 ). Interestingly, the innovative approaches of proteolysis targeting chimeras (PROTACs) and molecular glues might facilitate clinical cancer therapy ( Cruz Walma et al, 2022 ; Kung and Weber, 2022 ; Zhou and Xu, 2022 ).…”

“…Ubiquitination, also known as ubiquitylation, refers to the process by which ubiquitin (Ub, a small and highly conserved protein), with the help of a series of special enzymes, classifies proteins in cells, selects target proteins, and modifies those proteins ( McDowell and Philpott, 2016 ; Seeler and Dejean, 2017 ; Rape, 2018 ). Ubiquitination plays fundamental roles in many cellular events such as cell proliferation ( Kwon and Ciechanover, 2017 ; Werner et al, 2017 ; Senft et al, 2018 ; Song and Luo, 2019 ), cell cycle ( Teixeira and Reed, 2013 ; Darling et al, 2017 ; Gilberto and Peter, 2017 ), DNA repair ( Alpi and Patel, 2009 ; Abbas and Dutta, 2011 ), immune response ( Heaton et al, 2016 ; Rudnicka and Yamauchi, 2016 ; Manthiram et al, 2017 ), transcription ( Zhou et al, 2018 ; Imam et al, 2019 ; Sun et al, 2019 ), angiogenesis ( Zhang et al, 2022 ), metastasis ( Rossi and Rossi, 2022 ), and apoptosis ( Xu et al, 2017 ; Zhou et al, 2017 ).…”