Background
Introduction
Molecular features and biological functions of USP28
Substrates of USP28
Target of USP28 | Function of USP28 | The region and site involved | Results of the USP28 effects on the target | References |
---|---|---|---|---|
FBW7 (FBXW7) | Antagonizing its autocatalytic ubiquitination | – | Degradation of oncoproteins | [28] |
c-Myc | Countering the ubiquitination mediated by FBW7 | amino-terminus of FBW7; p–c-Myc-T58 | Promoting the cell cycle and glycolysis | |
MBI domain of MYC; USP28 Cys171 | Transactivating the SLUG promoter to enhance cancer stem-like traits | |||
c-Jun | Inhibiting the functions of FBW7, deubiquitinating and stabilizing c-Jun | – | Accelerating cell proliferation | [35] |
NICD1 | Repressing functions of FBW7, deubiquitinating NICD1 | – | Strengthening Notch signaling and influencing the secretory fate determination of intestine | [35] |
HIF-1α | Revising the destabilization caused by FBW7, and promoting its accumulation through c-Myc | Closely related to the GSK-3β phosphorylation sites | Expediting the angiogenesis | [25] |
Cyclin E1 | Loss of USP28 that contributes to the autoubiquitination of FBW7 and overexpression of USP28 can stabilize it | – | Promoting cell cycle progression | [34] |
STAT3 | Upregulating STAT3 and reversing the polyubiquitination mediated by FBW7 | – | Promoting cellular growth | [33] |
p53 | Deubiquitination p53 through antagonizing MDM2 | MDM2-catalyzed K48 ubiquitin chains | Inducing apoptosis | [26] |
ΔNp63 | Removing the K-48 linked ubiquitin chains independently of FBW7 | MDM2-catalyzed K48 ubiquitin chains | Facilitating cell proliferation and maintaining identity of squamous cancer cells | [25] |
LSD1 | Deubiquitinating and stabilizing it | An amine oxidase domain of LSD1; N-terminal region of USP28 | Suppressing differentiation, promoting cell proliferation and metastasis | |
CD44 | Removing ubiquitin group from CD44 protein and enhancing its stabilization | – | Maintaining the stem cell-like properties and promoting invasion | [36] |
H2A | Binding H2A and deubiquitinating it | ub-K119-H2A | Suppressing cell proliferation | [32] |
Claspin | Deubiquitinating and stabilizing it | – | Maintaining cell cycle arrest and cell survival in response of DNA damage caused by chemotherapy | [37] |
Snail | Stabilizing Snail | – | – | [82] |
Lin28A | Extending the half-life of Lin28A and stabilizing it | – | Promoting cell viability, colony formation and invasion | [74] |
ZNF304 | Decreasing ubiquitination of it | – | Switching of many tumor suppressor genes | [47] |
MDC1 | Leading to its stabilization | – | Promoting rescue from damage or contributing to apoptosis | [7] |
UCK1 | Antagonizing its ubiquitination caused by KLHL2 | K81 of UCK1 | Giving rise to the chemotherapeutic resistance to 5’AZA | [27] |
CHK2 | Turning over its ubiquitination mediated by PIRH2 | – | Enhancing the activation of G1/S and G2/M checkpoints | (141) |
Plk3 | Antagonizing the suppression function of SIAH2 | – | Inhibiting carcinogenesis | [111] |
FOXM1 | Directly interacting with it and promoting its stabilization | – | Promoting cell proliferation and inhibiting apoptosis | [4] |
Regulatory mechanisms of USP28 expression
Regulatory mechanisms of USP28’s actions
Oncogenic functions of USP28 in tumors
Effect of USP28 | Effect of USP28 on cancer hallmarks | Cancer type | Related mechanisms | The effects of USP28 expression in cancer prognosis | References |
---|---|---|---|---|---|
Promoting cancers | Promoting cell proliferation | Ovarian clear cell carcinoma | HNF-1β upregulates USP28, which gives rise to the high level of Claspin and CHK1 after the treatment of bleomycin | – | [37] |
High grade serous ovarian cancer | USP28 increases the level of Cyclin E1, which then promotes cell cycle | – | [34] | ||
Squamous cancer | Elevated USP28 upregulates ΔNp63 and participates in the process of pro-cancer with mediation of ΔNp63 | Negative | [15] | ||
Pancreatic cancer | USP28 stabilizes FOXM1 and then leads to the activation of Wnt/β-catenin pathway | Negative | [4] | ||
Lung cancer | USP28 deubiquitinates c-Myc, through which the activation of Cyclin D1-CDK6 complex is promoted. c-Myc is stabilized by USP28 and then increases HK2, PKM2 and LDHA, stimulating aerobic glycolysis | – | [14] | ||
USP28 enhances STAT3 signaling | Negative | [33] | |||
Breast cancer | Overexpression of HDAC5 reduces the polyubiquitination of USP28, contributing to the increase of LSD1 | – | [55] | ||
Colorectal cancer | USP28 maintains the expression of FOXC1 and then leads to the decrease of FBP1, enhancing aerobic glycolysis | – | [71] | ||
– | Lin28A brings about more colonies with the help of USP28 | – | [74] | ||
Initiating invasion and metastasis | Gastric cancer | USP28 contributes to higher N-cadherin while lower E-cadherin, leading to the stimulation of EMT | – | [83] | |
USP28 stabilizes Snail proteins which may then suppresses E-cadherin | – | ||||
– | Deubiquitination of Lin28A caused by USP28 promotes metastasis | – | [74] | ||
Breast cancer | Stabilization of LSD1 mediates the process that USP28 inhibits CLDN7 | – | [55] | ||
Inhibiting cell differentiation | Colorectal cancer | USP28 stabilizes NICD1 and maintain the activation of Notch signaling, leading to the suppression of cell differenciation | Negative | [35] | |
Breast cancer | USP28 deubiquitinates LSD1, and then differentiation gene p21Cif1/Waf1 reduces while pluripotency markers SOX2 and Oct4 increases | – | [9] | ||
– | USP28 enhances the suppression of let-7 induced by Lin28A, contributing to the suppression of cell differentiation | – | [74] | ||
Inducing angiogenesis | – | USP28 antagonizes the impact of FBW7 and inhibits the ubiquitination of HIF-1α | – | [25] | |
Esophageal cancer | c-Myc can be deubiquitinated by USP28 and then results in the accumulation of HIF-1α | – | [97] | ||
Maintaining cancer stem cell-like characteristics | Bladder cancer | Through upregulation USP28, ATG7 promotes the expression of CD44 | - | [36] | |
Breast cancer | USP28 contributes to the stabilization of c-myc, which stimulates the upregulation of SLUG and then maintains CSCs mediated by SOX9 | - | |||
USP28-LSD1 axis protects characteristics of CSCs | – | [9] | |||
Inhibiting cancers | Inhibiting cell proliferation | – | Knockdown of caspase-8 facilitates activation of USP28 which then brings about p53 stabilization | – | [26] |
– | USP28 decreases ub-K119-H2A, leading to the elevation of p53, p21 and p16INK4A | – | [32] | ||
– | USP28 turns over the ubiquitination of Plk3 possessing the ability to activate CHK2 and p53 | – | [111] | ||
Melanoma | USP28 reverses the auto-ubiquitination of FBW7, resulting in the decrease of BRAF and weakness of MAPK signaling | Positive | [16] | ||
Suppressing tumor invasion and metastasis | Breast cancer | USP28 reduces the accumulation of α-SMA while increases E-cadherin | Positive | [10] | |
Overexpression of USP28 leads to decrease of FN-1 and elevation of E-cadherin | – | [40] | |||
Melanoma | USP28 reverses the auto-ubiquitination of FBW7, resulting in the decrease of BRAF and weakness of MAPK signaling | Positive | [16] |
Promoting cell proliferation in tumorigenesis
Initiating invasion and metastasis in cancer
Inhibiting cancer cell differentiation
Inducing tumor angiogenesis
Maintaining cancer stem cell-like characteristics
Tumor-suppressive role of USP28 in carcinoma
Inhibiting cell proliferation in carcinogenesis
Suppressing tumor invasion and metastasis
Relationship between USP28 and tumor prognosis
Roles of USP28 in influencing therapy resistance
Potential drugs related to USP28 for cancer therapy
USP28 inhibitor | Cancer type | Cell lines | Kd value | IC50 value | References |
---|---|---|---|---|---|
[1,2,3]triazolo[4,5- d]pyrimidine (Compound 19) | Gastric cancer | HGC-27 cells | 40 nmol/L | 1.10 ± 0.02 μmol/L | [126] |
Streptoglutarimide H | Lung cancer | PC9 and H157 cells | – | – | [14] |
AZ1 | Lung squamous cancer | A-431 cells | – | 18.8 μM | [15] |
Lanatoside C | Gastric cancer | HEK 293 cells | – | – | [127] |
Isorhapontigenin | Bladder cancer | T24T cells | – | – | [36] |
Caffeic acid 3,4-dihydroxyphenethyl ester | Leukemia | Jurkat cells | – | – | [30] |
Vismodegib | Colorectal cancer | Ls174T and HCT116 cells | 1.42 ± 0.18 μM | 4.41 ± 1.08 μM | [21] |
FT206 | Lung squamous cancer | H520 cell | – | EC50 ~ 1–3 μM | [130] |