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USP8: a novel therapeutic target for Cushing’s disease

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Abstract

Cushing’s disease (CD), caused by an adrenocorticotropin-secreting pituitary adenoma, leads to hypercortisolemia and causes serious morbidity and increased mortality when suboptimally treated. Currently, the genetic events have rarely been reported in this disease. Recently, the recurrent activating mutations in the gene encoding ubiquitin-specific protease 8 (USP8) in CD have been independently reported by two teams. These hotspot mutations sustain epidermal growth factor receptor (EGFR) signaling and expand the pathogenic role of USP8 in corticotroph adenoma. This review summarizes current knowledge of USP8 and its substrate EGFR in cancer therapy and possible application of them in CD.

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References

  1. J. Newell-Price et al., Cushing’s syndrome. Lancet 367(9522), 1605–1617 (2006)

    Article  CAS  PubMed  Google Scholar 

  2. B.M. Biller et al., Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93(7), 2454–2462 (2008)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. A.B. Atkinson et al., Long-term remission rates after pituitary surgery for Cushing’s disease: the need for long-term surveillance. Clin. Endocrinol. 63(5), 549–559 (2005)

    Article  Google Scholar 

  4. C.G. Patil et al., Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J. Clin. Endocrinol. Metab. 93(2), 358–362 (2008)

    Article  CAS  PubMed  Google Scholar 

  5. F. Castinetti et al., Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J. Clin. Endocrinol. Metab. 94(9), 3400–3407 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. J. Jagannathan et al., Gamma Knife surgery for Cushing’s disease. J. Neurosurg. 106(6), 980–987 (2007)

    Article  PubMed  Google Scholar 

  7. C. de Bruin et al., Coexpression of dopamine and somatostatin receptor subtypes in corticotroph adenomas. J. Clin. Endocrinol. Metab. 94(4), 1118–1124 (2009)

    Article  PubMed  Google Scholar 

  8. D.L. Batista et al., The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J. Clin. Endocrinol. Metab. 91(11), 4482–4488 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. M. Boscaro et al., Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J. Clin. Endocrinol. Metab. 94(1), 115–122 (2009)

    Article  CAS  PubMed  Google Scholar 

  10. R. Pivonello et al., Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study. Clin. Endocrinol. 81(3), 408–417 (2014)

    Article  CAS  Google Scholar 

  11. A. Godbout et al., Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur. J. Endocrinol. 163(5), 709–716 (2010)

    Article  CAS  PubMed  Google Scholar 

  12. R. Pivonello et al., The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J. Clin. Endocrinol. Metab. 94(1), 223–230 (2009)

    Article  CAS  PubMed  Google Scholar 

  13. R. De Vecchis, C. Esposito, C. Ariano, Cabergoline use and risk of fibrosis and insufficiency of cardiac valves. Meta-analysis of observational studies. Herz 38(8), 868–880 (2013)

    Article  PubMed  Google Scholar 

  14. R.A. Feelders et al., Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N. Engl. J. Med. 362(19), 1846–1848 (2010)

    Article  CAS  PubMed  Google Scholar 

  15. F. Castinetti et al., Ketoconazole in Cushing’s disease: is it worth a try? J. Clin. Endocrinol. Metab. 99(5), 1623–1630 (2014)

    Article  CAS  PubMed  Google Scholar 

  16. M. Fleseriu et al., Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 97(6), 2039–2049 (2012)

    Article  CAS  PubMed  Google Scholar 

  17. D. Dworakowska, A.B. Grossman, The molecular pathogenesis of corticotroph tumours. Eur. J. Clin. Invest. 42(6), 665–676 (2012)

    Article  CAS  PubMed  Google Scholar 

  18. M. Reincke et al., Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47(1), 31–38 (2015)

    Article  CAS  PubMed  Google Scholar 

  19. L.G. Perez-Rivas et al., The gene of the ubiquitin-specific protease 8 is frequently mutated in adenomas causing Cushing’s disease. J. Clin. Endocrinol. Metab. 100(7), E997–E1004 (2015)

    Article  CAS  PubMed  Google Scholar 

  20. Z.Y. Ma et al., Recurrent gain-of-function USP8 mutations in Cushing’s disease. Cell Res. 25(3), 306–317 (2015)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. E. Mizuno, N. Kitamura, M. Komada, 14-3-3-dependent inhibition of the deubiquitinating activity of UBPY and its cancellation in the M phase. Exp. Cell Res. 313(16), 3624–3634 (2007)

    Article  CAS  PubMed  Google Scholar 

  22. I.M. Meijer et al., The Usp8 deubiquitination enzyme is post-translationally modified by tyrosine and serine phosphorylation. Cell Signal 25(4), 919–930 (2013)

    Article  CAS  PubMed  Google Scholar 

  23. S. Naviglio et al., UBPY: a growth-regulated human ubiquitin isopeptidase. EMBO J. 17(12), 3241–3250 (1998)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. D. Popovic, D. Vucic, I. Dikic, Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20(11), 1242–1253 (2014)

    Article  CAS  PubMed  Google Scholar 

  25. H. Tanno, M. Komada, The ubiquitin code and its decoding machinery in the endocytic pathway. J. Biochem. 153(6), 497–504 (2013)

    Article  CAS  PubMed  Google Scholar 

  26. A. Ciechanover, The unravelling of the ubiquitin system. Nat. Rev. Mol. Cell Biol. 16(5), 322–324 (2015)

    Article  CAS  PubMed  Google Scholar 

  27. S.M. Nijman et al., A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5), 773–786 (2005)

    Article  CAS  PubMed  Google Scholar 

  28. S. Hussain, Y. Zhang, P.J. Galardy, DUBs and cancer: the role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors. Cell Cycle 8(11), 1688–1697 (2009)

    Article  CAS  PubMed  Google Scholar 

  29. B. Nicholson et al., Deubiquitinating enzymes as novel anticancer targets. Future Oncol. 3(2), 191–199 (2007)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. N. Saini, A. Mahindra, Therapeutic strategies for the treatment of multiple myeloma. Discov. Med. 15(83), 251–258 (2013)

    PubMed  Google Scholar 

  31. E. Mizuno et al., Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Mol. Biol. Cell 16(11), 5163–5174 (2005)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. J.B. Johnston et al., Targeting the EGFR pathway for cancer therapy. Curr. Med. Chem. 13(29), 3483–3492 (2006)

    Article  CAS  PubMed  Google Scholar 

  33. Z. Zhang et al., EGFR-mutated lung cancer: a paradigm of molecular oncology. Oncotarget 1(7), 497–514 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  34. F. Ciardiello, G. Tortora, EGFR antagonists in cancer treatment. N. Engl. J. Med. 358(11), 1160–1174 (2008)

    Article  CAS  PubMed  Google Scholar 

  35. A.J. Mantha et al., Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. Clin. Cancer Res. 11(6), 2398–2407 (2005)

    Article  CAS  PubMed  Google Scholar 

  36. E. Kumaraswamy et al., BRCA1 regulation of epidermal growth factor receptor (EGFR) expression in human breast cancer cells involves microRNA-146a and is critical for its tumor suppressor function. Oncogene (2014). doi:10.1038/onc.2014.363

    PubMed  Google Scholar 

  37. M. Theodoropoulou et al., Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J. Endocrinol. 183(2), 385–394 (2004)

    Article  CAS  PubMed  Google Scholar 

  38. V.K. LeRiche, S.L. Asa, S. Ezzat, Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J. Clin. Endocrinol. Metab. 81(2), 656–662 (1996)

    CAS  PubMed  Google Scholar 

  39. G. Kontogeorgos et al., Localization of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFr) in human pituitary adenomas and nontumorous pituitaries: an immunocytochemical study. Endocr. Pathol. 7(1), 63–70 (1996)

    Article  CAS  PubMed  Google Scholar 

  40. H. Fukuoka et al., EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J. Clin. Invest. 121(12), 4712–4721 (2011)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. E. Lengyel et al., C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int. J. Cancer 113(4), 678–682 (2005)

    Article  CAS  PubMed  Google Scholar 

  42. I. Canadas et al., C-MET as a new therapeutic target for the development of novel anticancer drugs. Clin. Transl. Oncol. 12(4), 253–260 (2010)

    Article  CAS  PubMed  Google Scholar 

  43. A.T. De Oliveira et al., MET Is highly expressed in advanced stages of colorectal cancer and indicates worse prognosis and mortality. Anticancer Res. 29(11), 4807–4811 (2009)

    PubMed  Google Scholar 

  44. S. Dhillon, Gefitinib: a review of its use in adults with advanced non-small cell lung cancer. Target Oncol. 10(1), 153–170 (2015)

    Article  PubMed  Google Scholar 

  45. A. Tamiya et al., Phase II trial of carboplatin, S-1, and gefitinib as first-line triplet chemotherapy for advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations. Med. Oncol. 32(3), 40 (2015)

    Article  PubMed  Google Scholar 

  46. N. Singh, A. Jindal, D. Behera, Erlotinib usage after prior treatment with gefitinib in advanced non-small cell lung cancer: A clinical perspective and review of published literature. World J. Clin. Oncol. 5(5), 858–864 (2014)

    Article  PubMed Central  PubMed  Google Scholar 

  47. D.R. Camidge et al., Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13(10), 1011–1019 (2012)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. S. Byun et al., USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clin. Cancer Res. 19(14), 3894–3904 (2013)

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. A. Colao, S. Savastano, Medical treatment of prolactinomas. Nat. Rev. Endocrinol. 7(5), 267–278 (2011)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Grants to Qingfang Sun from National Natural Science Foundation of China (No: 81270856).

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Authors and Affiliations

  1. Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai, 200025, China

    Fangfang Jian, Liuguan Bian & Qingfang Sun

  2. Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Yanan Cao

  3. Department of Neurosurgery, Ruijin Hospital, Luwan Branch, Shanghai Jiao Tong University School of Medicine, No. 149, South Chongqing Road, Shanghai, 200025, China

    Qingfang Sun

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  1. Fangfang Jian
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  2. Yanan Cao
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  3. Liuguan Bian
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Correspondence to Liuguan Bian or Qingfang Sun.

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Jian, F., Cao, Y., Bian, L. et al. USP8: a novel therapeutic target for Cushing’s disease. Endocrine 50, 292–296 (2015). https://doi.org/10.1007/s12020-015-0682-y

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  • DOI: https://doi.org/10.1007/s12020-015-0682-y

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