USP6 explained

Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme^[1] that in humans is encoded by the hominid (i.e. found only in primates) USP6 gene^{[2] [3] [4]} located at band 13.2 on the short (i.e. "p") arm of chromosome 17 (notated as 17p13.2).^[5] Deubiquitinating enzymes (DUBs) are enzymes that act within cells to remove ubiquitins from various functionally important proteins. Ubiquitin enzymes add ubiquitin to these proteins and thereby regulate their cellular location, alter their activity, and/or promote their degradation. By deubiquitinating these proteins, DUBs counter the effects of the ubiquinating enzymes and contribute to regulating the actions of the targeted proteins.^[6] In normal adult tissues, USP6 is highly expressed in testicle tissue, modestly expressed in ovarian tissue, and absent or minimally expressed in other tissues.^[7] It is also highly expressed in fetal brain tissue. The specific functions of USP6 are poorly defined primarily because its presence is restricted to primates: there are no available animal models to determine the effects of its deletion, although some studies suggest that UPSP6 contributes to normal brain development.^[5] In all events, USP6 has gained wide interest because of its abnormally increased expression by the neoplastic cells in various tumors derived from mesenchymal tissue.

The USP6 gene associated with tumors is part of a fusion gene. Fusion genes are abnormal and potentially tumor-inducing genes formed by mergers between parts of two different genes as a result of large scale gene mutations such as chromosomal translocations, interstitial deletions, or inversions. For example, the USP6-COL1A1 fusion gene is formed by a translocation between part of the USP6 gene located at band 13.2 on the p arm of chromosome 17 and the COL1A1 gene located at band 21.33 on the q arm of this same chromosome.^[8] The USP6 gene has been documented to fuse with any one of scores of other genes and in doing so (as tested in many cases) create a fusion gene that is overproduced and contains high levels of deubiquitinating activity.^[9] Studies suggest that USP6-containing fusion genes cause or at least contribute to tumor development by inappropriately activating multiple cell signaling pathways including the Wnt signaling pathway, one of the JAK-STAT signaling pathways (i.e. the Jak1-STAT3 pathway), the c-Jun signaling pathway,^[10] and the NF-κB signaling pathway.^[11] All of these pathways, when inappropriately activated, have been implicated in promoting the development of tumors and cancers.^[10] The World Health Organization, 2021, classification of Tumors of Soft Tissue suggests that USP6-containing fusion protein-associated tumors are typically benign and usually self-limited in their growth.^[10] Furthermore, high levels of USP6 activity may act to suppress rather than promote tumor development in Ewing sarcoma, a tumor which has USP-containing fusion genes in ~1/3 of cases.^[1]

Tumor types that are associated with USP6-containing fusion genes and appear to promote their development and/or growth include:

• Aneurysmal bone cysts: Found in 59%^[12] to 75%^[13]
• Fibroma of tendon sheaths: Found in 6 out of 9 (67%) tested cases.^[14] of cases.
• Giant cell reparative granuloma (GCRG): GCRG are regarded as variants of aneurysmal bone cysts that occur in sites other than the jaw. An USP6-containing fusion gene was found in 8 of 9 (89%) GCRG tumors that were located in the hands or feet.^[12]
• Nodular fasciitis: Found in close to 90% of all cases.^[13]
• Myositis ossificans and fibro-osseous pseudotumor of digits: The World Health Organization, 2021, classified these two tumors as a single entity in the family of Fibroblastic and myofibroblastic tumors.^[15] USP6-containing fusion genes has been found in 8 of 9 (89%) tested cases of these tumors.^[16]

Further reading

• D'Andrea A, Pellman D . Deubiquitinating enzymes: a new class of biological regulators . Crit. Rev. Biochem. Mol. Biol. . 33 . 5 . 337–52 . 1999 . 9827704 . 10.1080/10409239891204251 .
• Nakamura T, Hillova J, Mariage-Samson R, etal . A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells . Oncogene . 7 . 4 . 733–41 . 1992 . 1565468 .
• Papa FR, Hochstrasser M . The yeast DOA4 gene encodes a deubiquitinating enzyme related to a product of the human tre-2 oncogene . Nature . 366 . 6453 . 313–9 . 1993 . 8247125 . 10.1038/366313a0 . 1993Natur.366..313P . 4273807 .
• Onno M, Nakamura T, Hillova J, Hill M . Identification of novel sequences in the repertoire of hypervariable TRE17 genes from immortalized nonmalignant and malignant human keratinocytes . Gene . 131 . 2 . 209–15 . 1993 . 8406013 . 10.1016/0378-1119(93)90295-E .
• Onno M, Nakamura T, Mariage-Samson R, etal . Human TRE17 oncogene is generated from a family of homologous polymorphic sequences by single-base changes . DNA Cell Biol. . 12 . 2 . 107–18 . 1993 . 8471161 . 10.1089/dna.1993.12.107 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Paulding CA, Ruvolo M, Haber DA . The Tre2 (USP6) oncogene is a hominoid-specific gene . Proc. Natl. Acad. Sci. U.S.A. . 100 . 5 . 2507–11 . 2003 . 12604796 . 10.1073/pnas.0437015100 . 151371 . 2003PNAS..100.2507P . free .
• Masuda-Robens JM, Kutney SN, Qi H, Chou MM . The TRE17 Oncogene Encodes a Component of a Novel Effector Pathway for Rho GTPases Cdc42 and Rac1 and Stimulates Actin Remodeling . Mol. Cell. Biol. . 23 . 6 . 2151–61 . 2003 . 12612085 . 10.1128/MCB.23.6.2151-2161.2003 . 149457 .
• Bizimungu C, De Neve N, Burny A, etal . Expression in a RabGAP yeast mutant of two human homologues, one of which is an oncogene . Biochem. Biophys. Res. Commun. . 310 . 2 . 498–504 . 2003 . 14521938 . 10.1016/j.bbrc.2003.09.051 .
• Oliveira AM, Hsi BL, Weremowicz S, etal . USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst . Cancer Res. . 64 . 6 . 1920–3 . 2004 . 15026324 . 10.1158/0008-5472.CAN-03-2827 . 15460680 .
• Oliveira AM, Perez-Atayde AR, Inwards CY, etal . USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts . Am. J. Pathol. . 165 . 5 . 1773–80 . 2004 . 15509545 . 10.1016/S0002-9440(10)63432-3 . 3278819.
• Martinu L, Masuda-Robens JM, Robertson SE, etal . The TBC (Tre-2/Bub2/Cdc16) Domain Protein TRE17 Regulates Plasma Membrane-Endosomal Trafficking through Activation of Arf6 . Mol. Cell. Biol. . 24 . 22 . 9752–62 . 2004 . 15509780 . 10.1128/MCB.24.22.9752-9762.2004 . 525471 .
• Oliveira AM, Perez-Atayde AR, Dal Cin P, etal . Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes . Oncogene . 24 . 21 . 3419–26 . 2005 . 15735689 . 10.1038/sj.onc.1208506 . free .
• Bizimungu C, Vandenbol M . At least two regions of the oncoprotein Tre2 are involved in its lack of GAP activity . Biochem. Biophys. Res. Commun. . 335 . 3 . 883–90 . 2005 . 16099424 . 10.1016/j.bbrc.2005.07.159 .
• Shen C, Ye Y, Robertson SE, etal . Calcium/calmodulin regulates ubiquitination of the ubiquitin-specific protease TRE17/USP6 . J. Biol. Chem. . 280 . 43 . 35967–73 . 2006 . 16127172 . 10.1074/jbc.M505220200 . free .
• Dechamps C, Bach S, Portetelle D, Vandenbol M . The Tre2 oncoprotein, implicated in Ewing's sarcoma, interacts with two components of the cytoskeleton . Biotechnol. Lett. . 28 . 4 . 223–31 . 2006 . 16555005 . 10.1007/s10529-005-5523-2 . 25625056 .

Notes and References

1. Henrich IC, Jain K, Young R, Quick L, Lindsay JM, Park DH, Oliveira AM, Blobel GA, Chou MM . Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation . Cancer Research . 81 . 8 . 2171–2183 . April 2021 . 33558334 . 10.1158/0008-5472.CAN-20-1458 . 8137534 .
2. Puente XS, Sanchez LM, Overall CM, Lopez-Otin C . Human and mouse proteases: a comparative genomic approach . Nat Rev Genet . 4 . 7 . 544–58 . Jul 2003 . 12838346 . 10.1038/nrg1111 . 2856065 .
3. Hoogendijk JE, Hensels GW, Gabreels-Festen AA, Gabreels FJ, Janssen EA, de Jonghe P, Martin JJ, van Broeckhoven C, Valentijn LJ, Baas F, etal . De-novo mutation in hereditary motor and sensory neuropathy type I . Lancet . 339 . 8801 . 1081–2 . May 1992 . 1349106 . 10.1016/0140-6736(92)90668-S . 35908066 .
4. Web site: Entrez Gene: USP6 ubiquitin specific peptidase 6 (Tre-2 oncogene).
5. Oliveira AM, Chou MM . The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma . Frontiers in Bioscience (Scholar Edition) . 4 . 1. 321–34 . January 2012 . 22202063 . 10.2741/271 . free .
6. Snyder NA, Silva GM . Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response . The Journal of Biological Chemistry . 297. 3. 101077 . August 2021 . 34391779 . 10.1016/j.jbc.2021.101077 . 8424594 . free .
7. Web site: USP6 ubiquitin specific peptidase 6 [Homo sapiens (Human)] - Gene - NCBI.
8. Stražar K, Šekoranja D, Matjašič A, Zupan A, Snoj Ž, Martinčič D, Pižem J . Intraarticular nodular fasciitis-detection of USP6 gene fusions in three cases by targeted RNA sequencing . Virchows Archiv . 478 . 6 . 1117–1124 . June 2021 . 33404853 . 10.1007/s00428-020-02991-6. 0945-6317 . 230783712 .
9. Legrand M, Jourdan ML, Tallet A, Collin C, Audard V, Larousserie F, Aubert S, Gomez-Brouchet A, Bouvier C, de Pinieux G . Novel partners of USP6 gene in a spectrum of bone and soft tissue lesions . Virchows Archiv . 479 . 1 . 147–156 . July 2021 . 33558945 . 10.1007/s00428-021-03047-z . 231850082 .
10. Nakayama S, Nishio J, Aoki M, Koga K, Nabeshima K, Yamamoto T . Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts . Cancer Genomics & Proteomics . 18 . 2 . 93–101 . 2021 . 33608306 . 7943209 . 10.21873/cgp.20244 .
11. Ye Y, Pringle LM, Lau AW, etal . TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NFκB . Oncogene . 29 . 25 . 3619–29 . June 2010 . 20418905 . 2892027 . 10.1038/onc.2010.116 .
12. Agaram NP, LeLoarer FV, Zhang L, Hwang S, Athanasian EA, Hameed M, Antonescu CR . USP6 gene rearrangements occur preferentially in giant cell reparative granulomas of the hands and feet but not in gnathic location . Human Pathology . 45 . 6 . 1147–52 . June 2014 . 24742829 . 4225080 . 10.1016/j.humpath.2014.01.020 .
13. Baumhoer D, Amary F, Flanagan AM . An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing . Genes, Chromosomes & Cancer . 58 . 2 . 88–99 . February 2019 . 30582658 . 10.1002/gcc.22699 . 58637942 .
14. Hiemcke-Jiwa LS, van Gorp JM, Fisher C, Creytens D, van Diest PJ, Flucke U . USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions . International Journal of Surgical Pathology . 28 . 8 . 816–825 . December 2020 . 32635781 . 10.1177/1066896920938878 . 220413896 . free .
15. Sbaraglia M, Bellan E, Dei Tos AP . The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives . Pathologica . 113 . 2 . 70–84 . April 2021 . 33179614 . 8167394 . 10.32074/1591-951X-213 .
16. Bekers EM, Eijkelenboom A, Grünberg K, Roverts RC, de Rooy JW, van der Geest IC, van Gorp JM, Creytens D, Flucke U . Myositis ossificans - Another condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst . Annals of Diagnostic Pathology . 34 . 56–59 . June 2018 . 29661729 . 10.1016/j.anndiagpath.2018.01.006 . 1854/LU-8559797 . 4957974 . free .