Table 1.
Deubiquitinases and cancer
| DUB name | Pathway/mechanism | Mutations and translocations | Published abnormalities in expression/protein level | Oncomine | |
|---|---|---|---|---|---|
| Upregulation | Downregulation | ||||
| USP1 | Deubiquitinates and negatively regulates FANCD2 and DNA repair (5). Also shown to deubiquitinate and inactivate PCNA, an important component of the DNA repair translesion synthesis pathway (6). | None reported | Upregulated in hydatidiform mole (7). | Brain, liver, cervical, gastric, sarcoma. (13 others) | Leukaemia, testicular, ovarian, prostate |
| USP2 | Upregulated in response to androgen, leading to stabilization of fatty acid synthase (8). Additionally deubiquitinates and stabilizes MDM2 (9). | 1/2 bladder cancer cell linesa | Overexpressed in ovarian carcinoma (10). Overexpressed and associated with poor prognosis in prostate cancer (8). | Brain | Brain, renal (3), HNSCC (2), Colon (2), lung. (3 others) |
| USP3 | Deubiquitinates histone H2A/H2B. Knockdown leads to defects in cell cycle progression and increased DNA damage (11). | None reported | None reported | Brain, bladder, prostate, HNSCC, testicular. (2 others) | Brain, leukaemia |
| USP4 | Transforms NIH 3T3 cells (12). Although known to bind to Rb (13), its mechanism of action remains unknown. A recent study has indicated it negatively regulates the WNT signaling pathway (14). | 1/2 bladder cancer cell linesa | Upregulated in adrenocortical carcinoma (15), small cell and adenoncarcinoma of the lung (16). Downregulation in small cell lung cancer cell lines (17). | Myeloma (2), liver, melanoma, brain, bladder. (1 other) | Testicular, lung (3), HNSCC (5), renal, brain. |
| USP5 | Knockdown leads to an increase in level and activity of p53 (18). Mechanism thought to be indirect and involve accumulation of free ubiquitin chains. | None reported | None reported. | Lung, colon(2), leukaemia, ovarian(2), liver. (2 others) | Brain (3), lymphoma, cervical |
| USP6 | Identified as oncogene through transformation of NIH 3T3 cells (19), mechanism unclear. Interacts with CDC2 and RAC1 to promote actin remodeling (20). TBC domain may regulate endosomal trafficking through activation of ARF6 (21). | Chromosomal translocations associated with aneurysmal bone cysts (22), usually but not exclusively, benign (23) | None reported | Myeloma, salivary gland, sarcoma | Brain (3), lymphoma, testis, myeloma, HNSCC. (1 other) |
| USP7 | Deubiquitinates and affects stability of both p53 and MDM2. Additionally involved in the regulation of localisation and activity of PTEN and FOXO (see text). | None reported | Increased expression in prostate cancer (24), However reduced expression reported in a study of NSCLC (25). | Colon, lung, testicular, myeloma, bladder (2). (5 others) | Brain, HNSCC, testicular, breast, melanoma. (3 others) |
| USP8 | Required for RTK downregulation following internalization, mechanism involving deubiquitination and stabilization of ESCRT components (26, 27, 28). | 1/11 lung cancer cell linesa | None reported | Brain (2), cervical, myeloma, lymphoma, brain. (1 other) | Leukaemia, lymphoma (2), testicular, lung (2) |
| USP9X | Interacts with and stabilizes beta‐catenin (29, 30). Also promotes TGF‐beta signaling through deubiquitination of SMAD4 (31). Additionally implicated in AMPK family kinase regulation. | None reported. | Overexpression reported in breast cancer (32). | Brain (2), gastric, cervical, colon, leukaemia. (3 others) | Brain, bladder, testicular, leukaemia (2), lymphoma (2) |
| USP11 | Deubiquitinates and stabilizes E7 (human papilloma virus (HPV) protein that targets Rb1‐ involved in pathogenesis of cervical cancer) (33). Interacts with BRCA2 (34) and stabilizes IkB (35). | None reported | None reported | Lung, myeloma, melanoma, HNSCC, skin. (1 other) | Brain (3), renal (2), testis, pancreas, HNSCC. (3 others) |
| USP15 | Deubiquitinates E6 (HPV protein which leads to ubiquitination and degradation of p53‐ involved in pathogenesis of cervical cancer) (36). Implicated in stabilization of APC (37). Associates with COP9 signalosome and has been shown to deubiquitinate IκB (38). | None reported | Downregulated in paclitaxel resistant ovarian cancer (39). | Vulva, brain, breast, lymphoma. | Brain, bladder, testicular, liver, melanoma. (3 others) |
| USP17 | Negatively regulates the activity of ras‐converting enzyme 1, thereby blocking ras membrane localisation and activation (40). | None reported | None reported | No available data | No available data |
| USP18 | Upregulates EGFR, mechanism uncertain but likely to occur at level of translation(41). Reported specificity for the ubiquitin‐like modifier ISG15 (42). | None reported | None reported | Bladder, ovarian, lung, brain, prostate. (1 other) | None |
| USP20 | Deubiquitinates and stabilizes HIF1‐alpha (43). | None reported | None reported | None | Lymphoma, leukaemia, testis, lung. |
| USP21 | Deubiquitinates histone H2A, activating transcription (44). | None reported | None reported | Leukaemia, bladder (2), liver, colon. | Testis, HNSCC. |
| USP22 | Deubiquitinates both Histone H2A and H2B, and is required for progression through cell cycle (45, 46). | None reported | Overexpressed and part of an 11‐gene signature that predicts poor prognosis in a wide range of malignancies (47). | Lung (2), bladder, leukaemia, melanoma, salivary. (4 others) | Brain (3), leukaemia (2), colon, liver, lymphoma. |
| USP28 | Required for MYC stability(48). Additionally stabilizes Chk2 and 53BP1 in response to DNA damage (49). | Somatic mutation reported in case of lobular breast cancer (50). 1/101 renal cell linesa. | Overexpression in colon and breast cancer (48). | Testicular, cervical, HNSCC, myeloma. | None |
| USP33 | Interacts with Robo1 and is required for Slit signaling (51, 52). | None reported | Overexpression in paediatric ALL (53). | Lung (2), lymphoma, Prostate (2), Myeloma, bladder. (1 other) | Brain (3), leukaemia (2), lung (3), breast. |
| USP39 | Involved in the mitotic spindle checkpoint, influences Aurora B expression, possibly through mRNA splicing (54). USP39 is catalytically inactive. | None reported | None reported | Leukaemia, ovarian, brain, lung, cervical. (6 others) | Brain, pancreas. |
| USP44 | Critical regulator of spindle checkpoint. Depletion of USP44 leads to defects in chromatin segregation (55) | 1/11 lung cancer cell linesa | None reported | Leukaemia. | Renal, brain, gastric, testis (2). |
| CYLD | Negative regulation of the NF‐κB pathway (see text). | Mutations (catalytic domain) in Cylindromatosis and trichoepithelioma. 1/128 lymphomaa | Several reports of down regulation in cancers including lung (56), liver (57), colon (57), multiple myeloma (58). Downregulation associated with progression in melanoma (59). | Leukaemia, renal (2), lung, testis, myeloma. (2 others) | Brain, ovarian, lung (3), HNSCC (2), bladder. (8 others) |
| AMSH | Involved in endosomal sorting/trafficking and promotes recycling of RTK from multivesicular body (60). Also reported as a positive regulator of BMP signaling (61). | None reported | None reported | Lung, liver, bladder, leukaemia (2), colon. (6 others) | Leukaemia (2) |
| AMSH‐LP | Potentiates TGFß signaling through interaction with inihibitory I‐SMADs (62) | None reported | None reported | Kidney (2), liver, brain, HNSCC. | Brain, testicular, leukaemia, brain. |
| BRCC36 | Component of the BRCA1 and BRCA2 containing complex (BRCC) involved in maintaining the G2 checkpoint and in the response to ionizing radiation (63). | Gene locus is at a chromosomal break point associated with translocations in T‐cell PLL (64). 3/36 lung cancer cell linesa | Overexpressed in breast cancer (63). | Lung, Testicular, colon, ovary, prostate. (6 others) | Brain (2). |
| MYSM1 | Deubiquitinates histone H2A and participates in androgen receptor dependant transcription (65). | None reported | None reported | Brain (2), testicular, HNSCC (2) | Brain. |
| POH1 | Component of the 19s proteasomal lid complex (66). Regulates ErbB2 ubiquitination, albeit without affecting its turnover (67). Deubiquitinates and stabilizes c‐jun (68). | None reported | None reported | Lung (3), colon, gastric, HNSCC (2), brain. (8 others) | Leukaemia (2), breast, lymphoma, testicular. |
| BAP1 | Discovered through its interaction with BRCA1 (69), BAP1 has poorly understood tumour suppressive functions. A recent study has shown interaction with the cell cycle regulator HCF‐1 to be critical (70). | Mutations and deletions in breast and lung cancer (69, 71, 72) | None reported | Testicular, lung (2), brain (2), kidney (2), cervical. (2 others) | Ovary, oesophageal, BCC, breast, lymphoma. (2 others) |
| UCHL1 | Function and mechanism of action uncertain (see text). | None reported (in cancer) | Upregulated in several malignancies (e.g. lung, colon) (73, 74, 75, 76, 77). However there have also been recent reports of methylation and reduced expression (see text). | Ovary, HNSCC (2), lung (3), gastric, oesophagus. (1 other) | Brain (2), ovarian, kidney, bladder, colon. (4 others) |
| UCHL5 | Reported to interact with SMADs and regulate TGFβ signaling (78). | None reported | None reported | Lung, breast, ovarian, vulva, parathyroid. | Brain, pancreas, breast. |
| OTUB1 | OTUB1 interacts with estrogen receptor alpha and negatively regulates ER‐alpha‐mediated transcription (79) | None reported | None reported | Bladder (3), lung, prostate, HNSCC, breast. (3 others) | Brain (2), HNSCC (2), Testis, Cervical, renal, sarcoma. (4 others) |
| A20 | Negative regulator of NF‐κB signaling (see text). | Chromosomal deletions and inactivating mutations found in several lymphoma subtypes (80, 81, 82, 83). 2 out of 11 lung cancera | Study showing overexpression in Hodgkins and anaplastic B‐cell lymphomas, with downregulation in other lymphoma types (84). | HNSCC (4), leukaemia (2), lung, brain (2), cervical. (6 others) | Bladder, ovary (2), lung, lymphoma (2), sarcoma. |
| Cezanne | Downregulates NF‐κB signalling through the deubiquitination and inactivation of RIP1 (85). | None reported | None reported | Liver, myeloma. | Ovarian. |
| TRABID | Positive regulator of WNT signaling required for TCF‐ mediated transcription (86). | 1/ 202 kidney cancer | None reported | Brain, testicular, leukaemia, oesophagus, liver. | Brain (2), leukaemia, liver, testicular, bladder. (2 others) |
Published data on DUB mutations and aberrations in expression remain sparse. A review of the COSMIC (Catalogue Of Somatic Mutations In Cancer http://www.sanger.ac.uk/genetics/CGP/cosmic (87)) and Oncomine (http://www.oncomine.org) (88) databases was therefore performed. Oncomine (Compedia bioscience, Ann Arbor, MI) was used for analysis and visualization of microarray data. Expression in cancer and normal tissue was compared, and studies in which statistically significant differences in expression (P < 10−4) are collated above. Up to five cancer types are named; further studies meeting the aforementioned criteria are numerated but not named. Tumour subtypes were not analysed. Together with differences in stage etc, this may explain the observation of both over and under‐expression within the same tumour group. Testicular refers to germ cell tumours of the testis.
a
Mutations identified by COSMIC, expressed as a fraction of tumours of that type that were assessed. Arf6, ADP ribosylation factor 6; BAP1, BRCA1 associated protein 1; BRCC36, BRCA1/BRCA2 containing complex subunit 3; HNSCC, Head and Neck Squamous Cell Carcinoma; Rb1, retinoblastoma 1; Robo1, Roundabout 1.