Biology:USP6

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Generic protein structure example

Ubiquitin carboxyl-terminal hydrolase 6 (USB6), also termed TRE17 and Tre-2, is a deubiquitinating enzyme[1] that in humans is encoded by the homanid (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]

References

  1. ↑ 1.0 1.1 "Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation". Cancer Research 81 (8): 2171–2183. April 2021. doi:10.1158/0008-5472.CAN-20-1458. PMID 33558334. 
  2. ↑ "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet 4 (7): 544–58. Jul 2003. doi:10.1038/nrg1111. PMID 12838346. 
  3. ↑ "De-novo mutation in hereditary motor and sensory neuropathy type I". Lancet 339 (8801): 1081–2. May 1992. doi:10.1016/0140-6736(92)90668-S. PMID 1349106. 
  4. ↑ "Entrez Gene: USP6 ubiquitin specific peptidase 6 (Tre-2 oncogene)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9098. 
  5. ↑ 5.0 5.1 "The TRE17/USP6 oncogene: a riddle wrapped in a mystery inside an enigma". Frontiers in Bioscience (Scholar Edition) 4 (1): 321–34. January 2012. doi:10.2741/271. PMID 22202063. 
  6. ↑ "Deubiquitinating enzymes (DUBs): regulation, homeostasis, and oxidative stress response". The Journal of Biological Chemistry 297 (3): 101077. August 2021. doi:10.1016/j.jbc.2021.101077. PMID 34391779. 
  7. ↑ "USP6 ubiquitin specific peptidase 6 [Homo sapiens (Human)] - Gene - NCBI". https://www.ncbi.nlm.nih.gov/gene/9098. 
  8. ↑ "Intraarticular nodular fasciitis-detection of USP6 gene fusions in three cases by targeted RNA sequencing". Virchows Archiv 478 (6): 1117–1124. June 2021. doi:10.1007/s00428-020-02991-6. ISSN 0945-6317. PMID 33404853. 
  9. ↑ "Novel partners of USP6 gene in a spectrum of bone and soft tissue lesions". Virchows Archiv 479 (1): 147–156. July 2021. doi:10.1007/s00428-021-03047-z. PMID 33558945. 
  10. ↑ 10.0 10.1 10.2 "Ubiquitin-specific Peptidase 6 (USP6)-associated Fibroblastic/Myofibroblastic Tumors: Evolving Concepts". Cancer Genomics & Proteomics 18 (2): 93–101. 2021. doi:10.21873/cgp.20244. PMID 33608306. 
  11. ↑ "TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NFκB". Oncogene 29 (25): 3619–29. June 2010. doi:10.1038/onc.2010.116. PMID 20418905. 
  12. ↑ 12.0 12.1 "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. doi:10.1016/j.humpath.2014.01.020. PMID 24742829. 
  13. ↑ 13.0 13.1 "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. doi:10.1002/gcc.22699. PMID 30582658. https://discovery.ucl.ac.uk/id/eprint/10085300/. 
  14. ↑ "USP6-Associated Neoplasms: A Rapidly Expanding Family of Lesions". International Journal of Surgical Pathology 28 (8): 816–825. December 2020. doi:10.1177/1066896920938878. PMID 32635781. 
  15. ↑ "The 2020 WHO Classification of Soft Tissue Tumours: news and perspectives". Pathologica 113 (2): 70–84. April 2021. doi:10.32074/1591-951X-213. PMID 33179614. 
  16. ↑ "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. doi:10.1016/j.anndiagpath.2018.01.006. PMID 29661729. 

Further reading




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