Table 1.
The list of DUBs involved in GC.
| DUBs | Upstream Regulatory Events | Substrate(s) | Biological Effects | Ref. |
|---|---|---|---|---|
| USPs | ||||
| USP1 | None reported | None reported | USP1 silencing hindered the proliferation, migration, and invasion of GC cells. | [17] |
| None reported | ID2 | USP1 promoted GC metastasis by stabilizing ID2. | [18] | |
| USP2 | None reported | E2F4 | USP2 promoted GC progression by facilitating E2F4/autophagy/zinc homeostasis axis. | [19] |
| USP3 | None reported | None reported | USP3 promoted GC cell proliferation and spreading by regulating cell-cycle-control- and EMT-related molecules. | [20] |
| TGF-β upregulates USP3 expression | SUZ12 | USP3 promoted GC metastasis by stabilizing SUZ12. | [21] | |
| None reported | COL9A3/COL6A5 | USP3 promoted GC cell migration, invasion, and EMT via binding to and deubiquitinating COL9A3 and COL6A5. | [22] | |
| Hsa_circ_0017639 upregulates USP3 expression by sponging miR-224-5p | None reported | Hsa_circ_0017639 participates in GC progression by regulating the miR-224-5p/USP3 axis. | [23] | |
| LncRNA SND1-IT1 functions as a ceRNA to upregulate USP3 expression via absorbing miR-1245b-5p and simultaneously recruiting DDX54 to enhance USP3 mRNA stability | SNAIL1 | Exosomal SND1-IT1 from GC cells upregulated USP3 expression, thus mediating SNAIL1 stabilization and accelerating the migration and invasion of gastric mucosa cells. | [24] | |
| USP7 | None reported | USP11, PPM1G, DHX40, DDX24 and TRIP12 | Unclear | [25] |
| None reported | PD-L1 | USP7 served as an upstream DUB of PD-L1; USP7 abrogation hindered GC cell growth by downregulating PD-L1-mediated immunosuppression and enhanced cell cycle arrest simultaneously by stabilizing p53. | [26] | |
| Cisplatin and paclitaxel promoted USP7 expression in CAFs | hnRNPA1 | Cisplatin and paclitaxel promoted the secretion of miR-522 from CAFs by activating USP7/hnRNPA1 axis, resulting in ferroptosis suppression, and acquired chemoresistance by inhibiting ALOX15 expression and lipid-ROS accumulation in GC cells. | [27] | |
| USP9X | None reported | None reported | USP9X was overexpressed and predicted poorer survival in GC. | [28] |
| Hsa_circ_0008434 enhances USP9X expression by sponging miR-6838-5p | None reported | Hsa_circ_0008434 promoted GC proliferation, invasion, and migration by regulating miR-6838-5p/USP9X axis. | [29] | |
| None reported | YAP | The LINC01433-YAP feedback loop promoted GC cell proliferation, migration, invasion, and chemotherapy resistance. LINC01433 increased the stability but decreased the phosphorylation of YAP by enhancing its interaction with USP9X and attenuating its interaction with LATS1, respectively. | [30] | |
| USP10 | None reported | None reported | USP10 was an independent prognostic marker for patients with GC. | [31] |
| 3-Deazaneplanocin A treatment upregulates USP10 expression by reducing EZH2 binding on its promoter | p53 | Stabilization of p53 by USP10 seemed to be correlated with the sensitivity of GC cells to 3-Deazaneplanocin A. | [32] | |
| CircCOL1A2 upregulates USP10 expression by sponging miR-1286 | RFC2 | CircCOL1A2 sponges miR-1286 to promote GC cell migration and invasion by increasing USP10 level to stabilize RFC2. | [33] | |
| USP11 | None reported | None reported | USP11 overexpression promoted proliferation and migration and alleviated paclitaxel’s toxicity in GC cells by inhibiting RhoA and Ras signaling. | [34] |
| USP13 | None reported | None reported | High expression of USP13 predicted poor prognosis in GC. | [35] |
| None reported | Snail | USP13 promoted the EMT and metastasis of GC cells by stabilizing Snail. | [36] | |
| USP14 | miR-320a inhibits USP14 expression by targeting its 3′-UTR | Vimentin | USP14-mediated deubiquitination of vimentin enhanced the aggressiveness of GC cells, and miR-320a served as a tumor suppressor by inhibiting both USP14 and vimentin. | [37] |
| None reported | None reported | USP14 silencing sensitized GC cells to cisplatin by impeding Akt/ERK signaling pathways. | [38] | |
| YTHDF1 enhanced USP14 protein translation in a m6A-dependent manner | None reported | YTHDF1 promoted GC progression and metastasis by promoting USP14 protein translation in an m6A-dependent manner. | [39] | |
| USP15 | None reported | None reported | USP15 overexpression inhibited GC cell proliferation, migration, and invasion. | [40] |
| None reported | None reported | USP15 promoted GC progression through the Wnt/β-catenin signaling pathway. | [41] | |
| USP15 is potential regulated by LINC00205/miR-26a axis | None reported | Unclear | [42] | |
| USP20 | None reported | None reported | USP20 inhibited GC cell growth and G1/S cell cycle transition by regulating Claspin. | [43] |
| USP21 | None reported | GATA3 | USP21 upregulated MAPK1 expression by stabilizing GATA3 to promote GC cell growth and stemness. | [44] |
| USP22 | None reported | None reported | Coordinate expression of USP22 and BMI1 correlated with GC progression and treatment failure. | [45] |
| None reported | None reported | High expression of USP22 correlated with GC progression and has synergistic effects with c-Myc. | [46] | |
| None reported | BMI1 | USP22 contributed to gastric CSC stemness maintenance and GC progression by stabilizing BMI1. | [47] | |
| None reported | None reported | USP22 siRNA-loaded nanoliposomes decorated with CD44 antibodies selectively target and eliminate CD44+ GC stem cells. | [48] | |
| None reported | None reported | Positive co-expression of USP22 and HSP90 might be more effective in predicting prognosis of GC. | [49] | |
| None reported | None reported | USP22 promotes GC progression and metastasis through c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling. | [50] | |
| POU2F1 upregulates USP22 expression by suppressing the expression of miR-4490 | None reported | POU2F1-miR-4490-USP22 signaling axis plays a significant role in GC development and progression. | [51] | |
| None reported | None reported | USP22 overexpression in GC induces the upregulation of SOS1 and activation of the RAS/ERK and PI3K/AKT pathways. | [52] | |
| USP28 | None reported | None reported | USP28 promoted cell proliferation and metastasis of GC cells by regulating LSD1. | [53] |
| USP29 | TGFβ, TNFα, and hypoxia induced the transcription of USP29 | Snail | USP29 cooperated with SCP1 to prevent Snail degradation and further promoted GC cell metastasis. | [54] |
| USP32 | None reported | SMAD2 | USP32 is involved in GC development and chemoresistance through the upregulation of SMAD2. | [55] |
| USP33 | None reported | None reported | USP33 overexpression inhibited GC cell proliferation, migration, and invasion. | [56] |
| None reported | ROBO1 | USP33 contributed to SLIT2-ROBO1 axis in inhibiting GC cell migration and EMT process. | [57] | |
| DUB1 | None reported | TAZ | DUB1 stabilized TAZ protein and promoted GC progression via the Hippo/TAZ axis. | [58] |
| USP37 | PLAGL2 activated USP37 transcription | Snail | USP37, which is transcriptionally activated by PLAGL2, deubiquitinates and stabilizes Snail1 to promote the proliferation, EMT, and metastasis of GC cells. | [59] |
| USP39 | None reported | None reported | USP39 silencing inhibited the growth of GC cells via PARP activation. | [60] |
| miR-133a inhibited USP39 expression by targeting its 3′-UTR | None reported | miR-133a suppressed GC proliferation by regulating USP39. | [61] | |
| USP42 | None reported | None reported | USP42 depression inhibited GC cell proliferation and invasion. | [62] |
| USP44 | None reported | None reported | USP44 overexpression resulted in DNA aneuploidy. | [63] |
| CircFOXO3 upregulates USP44 expression by sponging miR-143-3p | None reported | CircFOXO3 promoted GC cells proliferation and migration by increasing USP44 expression through targeting miR-143-3p. | [64] | |
| USP47 | miR-204-5p inhibited USP47 expression via binding its 3′-UTR | None reported | MiR-204-5p functioned as a tumor suppressor in GC by suppressing USP47 and RAB22A. | [65] |
| None reported | None reported | USP47 regulates NF-κB activity by stabilizing β-TrCP and contributes to chemoresistance of GC cells. | [66] | |
| USP49 | USP49 was transcriptionally activated by the YAP1/TEAD4 complex | YAP1 | USP49 and YAP1 form a positive feedback loop to promote malignant progression of GC. | [67] |
| CYLD | miR-362 inhibited CYLD expression via targeting its 3′-UTR | None reported | Upregulated miR-362 promoted GC cell proliferation and cisplatin resistance by repressing CYLD and activating NF-κB signaling. | [68] |
| miR-500 inhibited CYLD expression via targeting its 3′-UTR | None reported | Upregulated miR-500 promoted GC cell proliferation and cisplatin resistance by repressing CYLD, OTUD7B, and TAX1BP1 and activating NF-κB signaling. | [69] | |
| miR-130b inhibited CYLD expression via targeting its 3′-UTR | None reported | Upregulated miR-130b promoted GC cell proliferation and inhibited apoptosis by repressing CYLD. | [70] | |
| miR-20a negatively regulated CYLD expression by targeting its 3′ UTR | None reported | Upregulated miR-20a augmented the resistance of GC cells to cisplatin by inhibiting CYLD and activating NF-κB signaling and its downstream targets. | [71] | |
| miR-425-5p negatively regulated CYLD expression by targeting its 3′ UTR | None reported | Upregulated miR-425-5p may promote GC cell migration and invasion by repressing CYLD. | [72] | |
| CYLD expression was inversely correlated with hypermethylation of its promoter, which could be induced by some infectious agents | None reported | Decreased CYLD level may be associated with gender, patient’s age, high grade, and no lymph-node metastasis in GC patients. | [73] | |
| LncRNA CRAL functions as a ceRNA to upregulate CYLD expression via absorbing miR-505 | None reported | LncRNA CRAL improved cisplatin resistance via the miR-505/CYLD/AKT axis in GC cells. | [74] | |
| miR-454 inhibited CYLD expression via targeting its 3′-UTR | None reported | miR-454 supported survival and induced oxaliplatin resistance in GC cells by repressing CYLD. | [75] | |
| Exosomal miR-588 from M2 polarized macrophages inhibited CYLD expression via targeting its 3′-UTR | None reported | Exosomal miR-588 contributed to cisplatin GC cell resistance by repressing CYLD. | [76] | |
| ZNF333 decreased CYLD level by binding to its promoter | None reported | ALKBH5 promoted the process of bile-acid-induced gastric intestinal metaplasia by ZNF333/CYLD/CDX2 pathway. | [77] | |
| UCHs | ||||
| UCHL1 | UCHL1 may be epigenetically inactivated via promoter methylation | None reported | UCHL1 methylation was correlated with poor clinical outcome in GC patients. | [78,79,80,81,82] |
| None reported | None reported | UCHL1 promoted GC cell proliferation and metastasis by activating the Akt and ERK1/2 pathways. | [83] | |
| None reported | None reported | UCHLI silencing inhibited GC cell proliferation and metastasis. | [84] | |
| UCHL3 | None reported | None reported | UCHL3 stimulated GC metastasis by upregulating IGF2. | [85] |
| UCHL5 | None reported | None reported | A certain subgroup of GC patients with high expression of UCHL5 had better prognosis. | [86] |
| None reported | NFRKB | LncRNA DRAIC inhibited GC proliferation and metastasis by mediating ubiquitination degradation of NFRKB by interfering with its combination with UCHL5. | [87] | |
| BAP1 | None reported | None reported | BAP1 downregulation predicts unfavorable survival in GC. | [88] |
| OTUs | ||||
| OTUB1 | None reported | None reported | OTUB1 enhanced tumor invasiveness and predicted a poor prognosis in GC. | [89] |
| OTUB2 | None reported | KRT80 | OTUB2 enhanced KRT80 stability via deubiquitination and promoted GC proliferation. | [90] |
| None reported | KDM1A | OTUB2 promoted GC tumorigenesis by enhancing KDM1A-mediated stem cell-like properties. | [91] | |
| A20 | A20 expression was inversely correlated with methylation at specific CpG sites in its intronic region | None reported | Increased A20 levels were associated with poor clinical outcomes. | [92] |
| None reported | None reported | A20 depletion inhibited the capacity of proliferation, migration, and invasion of GC cells. | [93] | |
| miR-200a inhibited A20 expression by targeting its 3′-UTR | RIP1 | miR-200a prevented RIP1 polyubiquitination and enhanced TRAIL sensitivity by targeting A20 in GC cells. | [94] | |
| H. pylori-induced NF-κB activation elevated A20 expression | Procaspase-8 | Increased A20 expression by USP48 inhibited K63-linked ubiquitinylation of procaspase-8, restricting caspase-8 activity and apoptosis in GC cells. | [95,96,97,98] | |
| H. pylori infection decreased A20 expression by upregulating miR-29a-3p | None reported | A20 silencing promoted gastric epithelial cell migration. | [99] | |
| JAMMs | ||||
| PSMD14 | None reported | PTBP1 | PSMD14 stabilized PTBP1 to promote GC cell proliferation and invasion. | [100] |
| CSN5 | None reported | RUNX3 | CSN5 facilitates nuclear export and degradation of RUNX3. | [101] |
| None reported | None reported | CSN5 knockdown inhibited proliferation and promoted apoptosis of GC cells by regulating p53-related apoptotic pathways. | [102] | |
| None reported | p14ARF | CSN5 potentiated GC progression by decreasing p14ARF expression through non-ubiquitin pathway. | [103] | |
| The activity of CSN5 was enhanced by IKKβ, and IKKβ expression was inhibited by DAPK1 | PD-L1 | Overexpression of DAPK1 enhanced NK cell killing and suppressed tumor immune evasion in GC cells by inhibiting the IKKβ/CSN5/PD-L1 axis. | [104] | |
| BRCC3 | LncRNA TMPO-AS1 functions as a ceRNA to upregulate BRCC3 expression via absorbing miR-126-5p | None reported | TMPO-AS1 accelerated GC cell proliferation, migration, and angiogenesis by regulating miR-126-5p/BRCC3 axis and activating PI3K/Akt/mTOR signaling. | [105] |
| MJDs | ||||
| Ataxin-3 | None reported | None reported | Decreased Ataxin-3 expression correlated with clinicopathologic features of GC. | [106] |