The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond

Abstract

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Keywords: USP36; cancer; deubiquitinating enzyme; ubiquitination.

Figure 1

The structure of USP36. (a) Comparison of the domain structures of putative USPs. (b) The structure of USP36 is predicated by AlphaFold, and its USP domains (amino acid residues 122–423) are labeled in red.

Figure 2

The overview of USP36-mediated signaling pathways. (A) Hippo/YAP signaling. USP36 stabilizes the YAP protein by inhibiting the polyubiquitination of the K48 chain of the YAP protein. First, USP36 binds to the YAP protein to form a stable complex. Second, USP36 prevents the degradation of YAP protein by inhibiting the polyubiquitination of the K48 chain of YAP protein. Finally, stable YAP protein can continue to participate in the regulation of Hippo/YAP signaling pathway, thereby affecting the growth and differentiation of cells. (B) PRL1/Snail2 signaling. In glioblastoma (GBM), PRL1 promotes tumor invasion and metastasis by activating USP36-mediated deubiquitination of Snail2. (C) c-Myc/SOD2 signaling. Overexpression of USP36 is accompanied by increased levels of c-Myc and SOD2 proteins, attenuating ischemia-induced ubiquitination of these two proteins. (D) CEP63/YAP1 signaling. USP36 can promote YAP1 expression by binding to CEP63 and inhibiting K63 ubiquitination degradation of FXR1, thereby enhancing cancer stem cell properties. (E) ERK/AKT signaling. USP36 regulates the stability of PM-1. Through deubiquitination, USP36 decreases the expression level of PME-1 and promotes the activation of ERK and Akt signaling pathways. (F) ALR/MDM2 signaling. MDM2 promotes the degradation of ALR proteins by ubiquitinating them, while USP36 maintains the stability of ALR proteins by removing ubiquitination modifications. (G) PARP1 signaling. Dox promotes the progression of DIC by activating USP36-mediated deubiquitination of PARP1. This figure was produced by Biorender (Agreement number: YM26R6CFJU).

Figure 3

The role of USP36 in non-cancerous diseases. This figure was produced by Biorender (Agreement number: JM26L98JPQ).

Figure 4

The expression of USP36 RNA and proteins in various human tissues. Available online: https://www.proteinatlas.org/ENSG00000055483-USP36/tissue#rna_expression (accessed on 25 February 2024).

Figure 5

Analysis of the correlation between USP36 expression level and overall survival using Kaplan–Meier test and log-rank test. Esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), liver hepatocellular carcinoma (LIHC), kidney renal clear cell carcinoma (KIRC). Available online: GEPIA (http://gepia.cancer-pku.cn/, 25 February 2024).

Figure 6

The regulating mechanisms of USP36 in various cancers. This figure was produced by BioRender. (Agreement number: ET26L9E69R).

Figure 7

The protein–protein interaction network of USP36 as predicted by the GeneMANA Server.