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A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance

Abstract

Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.

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Fig. 1: GRP75 interacts with SIX1 in PC cells.
Fig. 2: GRP75 inhibits K48-linked ubiquitination and degradation of SIX1.
Fig. 3: GRP75-USP1 interacts with SIX1 in the cytoplasm.
Fig. 4: USP1 deubiquitinates and stabilizes SIX1 in PC.
Fig. 5: Inhibition of GRP75-USP1 induces proliferative suppression of PC cells in a SIX1-dependent manner.
Fig. 6: GRP75-USP1 knockdown inhibits PC growth in vivo.
Fig. 7: GRP75-USP1-SIX1 axis promotes CRPC development.
Fig. 8: GRP75 and USP1 are positively correlated with SIX1.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Culig Z, Santer FR. Androgen receptor signaling in prostate cancer. Cancer Metastasis Rev. 2014;33:413–27.

    Article  CAS  Google Scholar 

  3. Fizazi K, Kramer G, Eymard JC, Sternberg CN, de Bono J, Castellano D, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020; https://doi.org/10.1016/S1470-2045(20)30449-6.

  4. Fushimi C, Tada Y, Takahashi H, Nagao T, Ojiri H, Masubuchi T, et al. A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma. Ann Oncol. 2018;29:979–84.

    Article  CAS  Google Scholar 

  5. Saad F, Sternberg CN, Efstathiou E, Fizazi K, Modelska K, Lin X, et al. Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: any Rise in Prostate-specific Antigen May Require Closer Monitoring. Eur Urol. 2020; https://doi.org/10.1016/j.eururo.2020.08.025.

  6. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371:1028–38.

    Article  Google Scholar 

  7. Tian S, Lei Z, Gong Z, Sun Z, Xu D, Piao M. Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review. Cancer Cell Int. 2020;20:409.

    Article  Google Scholar 

  8. Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247–54.

    Article  CAS  Google Scholar 

  9. Wu K, Li Z, Cai S, Tian L, Chen K, Wang J, et al. EYA1 phosphatase function is essential to drive breast cancer cell proliferation through cyclin D1. Cancer Res. 2013;73:4488–99.

    Article  CAS  Google Scholar 

  10. Zhu Z, Rong Z, Luo Z, Yu Z, Zhang J, Qiu Z, et al. Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis. Mol Cancer. 2019;18:126.

    Article  Google Scholar 

  11. Li L, Liang Y, Kang L, Liu Y, Gao S, Chen S, et al. Transcriptional Regulation of the Warburg Effect in Cancer by SIX1. Cancer Cell. 2018;33:368–85.

    Article  CAS  Google Scholar 

  12. Behbakht K, Qamar L, Aldridge CS, Coletta RD, Davidson SA, Thorburn A, et al. Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res. 2007;67:3036–42.

    Article  CAS  Google Scholar 

  13. Ng KT, Man K, Sun CK, Lee TK, Poon RT, Lo CM, et al. Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma. Br J Cancer. 2006;95:1050–5.

    Article  CAS  Google Scholar 

  14. Zeng J, Shi R, Cai CX, Liu XR, Song YB, Wei M, et al. Increased expression of Six1 correlates with progression and prognosis of prostate cancer. Cancer Cell Int. 2015;15:63.

    Article  Google Scholar 

  15. Burress H, Kellner A, Guyette J, Tatulian SA, Teter K. HSC70 and HSP90 chaperones perform complementary roles in translocation of the cholera toxin A1 subunit from the endoplasmic reticulum to the cytosol. J Biol Chem. 2019;294:12122–31.

    Article  CAS  Google Scholar 

  16. Liao Y, Liu Y, Xia X, Shao Z, Huang C, He J, et al. Targeting GRP78-dependent AR-V7 protein degradation overcomes castration-resistance in prostate cancer therapy. Theranostics. 2020;10:3366–81.

    Article  CAS  Google Scholar 

  17. Murata S, Minami Y, Minami M, Chiba T, Tanaka K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2001;2:1133–8.

    Article  CAS  Google Scholar 

  18. Ryu SW, Stewart R, Pectol DC, Ender NA, Wimalarathne O, Lee JH, et al. Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells. PLoS Biol. 2020;18:e3000606.

    Article  CAS  Google Scholar 

  19. Chauhan D, Tian Z, Nicholson B, Kumar KG, Zhou B, Carrasco R, et al. A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Cancer Cell. 2012;22:345–58.

    Article  CAS  Google Scholar 

  20. He L, Liu X, Yang J, Li W, Liu S, Liu X, et al. Imbalance of the reciprocally inhibitory loop between the ubiquitin-specific protease USP43 and EGFR/PI3K/AKT drives breast carcinogenesis. Cell Res. 2018;28:934–51.

    Article  CAS  Google Scholar 

  21. Liang Q, Dexheimer TS, Zhang P, Rosenthal AS, Villamil MA, You C, et al. A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses. Nat Chem Biol. 2014;10:298–304.

    Article  CAS  Google Scholar 

  22. Lim KS, Li H, Roberts EA, Gaudiano EF, Clairmont C, Sambel LA, et al. USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors. Mol Cell. 2018;72:925–41.

    Article  CAS  Google Scholar 

  23. Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014;14:263–76.

    Article  CAS  Google Scholar 

  24. Starenki D, Hong SK, Lloyd RV, Park JI. Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene. 2015;34:4624–34.

    Article  CAS  Google Scholar 

  25. Wu PK, Hong SK, Chen W, Becker AE, Gundry RL, Lin CW, et al. Mortalin (HSPA9) facilitates BRAF-mutant tumor cell survival by suppressing ANT3-mediated mitochondrial membrane permeability. Sci Signal. 2020;13.

  26. Wu PK, Hong SK, Starenki D, Oshima K, Shao H, Gestwicki JE, et al. Mortalin/HSPA9 targeting selectively induces KRAS tumor cell death by perturbing mitochondrial membrane permeability. Oncogene. 2020;39:4257–70.

    Article  CAS  Google Scholar 

  27. Wu PK, Hong SK, Veeranki S, Karkhanis M, Starenki D, Plaza JA, et al. A mortalin/HSPA9-mediated switch in tumor-suppressive signaling of Raf/MEK/extracellular signal-regulated kinase. Mol Cell Biol. 2013;33:4051–67.

    Article  CAS  Google Scholar 

  28. Christensen KL, Brennan JD, Aldridge CS, Ford HL. Cell cycle regulation of the human Six1 homeoprotein is mediated by APC(Cdh1). Oncogene. 2007;26:3406–14.

    Article  CAS  Google Scholar 

  29. Tucci M, Caffo O, Buttigliero C, Cavaliere C, D’Aniello C, Di Maio M, et al. Therapeutic options for first-line metastatic castration-resistant prostate cancer: Suggestions for clinical practise in the CHAARTED and LATITUDE era. Cancer Treat Rev. 2019;74:35–42.

    Article  CAS  Google Scholar 

  30. Wen S, He Y, Wang L, Zhang J, Quan C, Niu Y et al. Aberrant activation of super enhancer and choline metabolism drive antiandrogen therapy resistance in prostate cancer. Oncogene. 2020; https://doi.org/10.1038/s41388-020-01456-z.

  31. Liao Y, Liu N, Hua X, Cai J, Xia X, Wang X, et al. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor. Cell Death Dis. 2017;8:e2585.

    Article  CAS  Google Scholar 

  32. Liao Y, Xia X, Liu N, Cai J, Guo Z, Li Y, et al. Growth arrest and apoptosis induction in androgen receptor-positive human breast cancer cells by inhibition of USP14-mediated androgen receptor deubiquitination. Oncogene. 2018;37:1896–910.

    Article  CAS  Google Scholar 

  33. Xia X, Liao Y, Huang C, Liu Y, He J, Shao Z, et al. Deubiquitination and stabilization of estrogen receptor alpha by ubiquitin-specific protease 7 promotes breast tumorigenesis. Cancer Lett. 2019;465:118–28.

    Article  CAS  Google Scholar 

  34. Li Z, Tian T, Lv F, Chang Y, Wang X, Zhang L, et al. Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PLoS ONE. 2013;8:e59203.

    Article  CAS  Google Scholar 

  35. Yi X, Luk JM, Lee NP, Peng J, Leng X, Guan XY, et al. Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol Cell Proteom. 2008;7:315–25.

    Article  CAS  Google Scholar 

  36. Chen Z, Wu D, Thomas-Ahner JM, Lu C, Zhao P, Zhang Q, et al. Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci USA. 2018;115:6810–5.

    Article  CAS  Google Scholar 

  37. Liao Y, Liu N, Xia X, Guo Z, Li Y, Jiang L, et al. USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia. Cell Disco. 2019;5:24.

    Article  Google Scholar 

  38. Liao Y, Guo Z, Xia X, Liu Y, Huang C, Jiang L, et al. Inhibition of EGFR signaling with Spautin-1 represents a novel therapeutics for prostate cancer. J Exp Clin Cancer Res. 2019;38:157.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (82072810, 82002481, 81972399), the Science and Technology Program of Guangzhou (202002030107), projects from Foundation for Higher Education of Guangdong (2019KQNCX113), Special fund of Foshan Summit plan (2019D001), Grant from Foshan Science technology and Medical foundation (1920001000958) and Guangzhou key medical discipline construction project fund.

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HBH and JBL designed the experiments. YNL, YL, ZLS, XHX, YFD, JYC, LYY, JCH, CFY, TMH, WSS and FL performed the experiments, HBH, JBL and DLT wrote the paper. All authors read and approved the final paper.

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Correspondence to Jinbao Liu or Hongbiao Huang.

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Liao, Y., Liu, Y., Shao, Z. et al. A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance. Oncogene 40, 4291–4306 (2021). https://doi.org/10.1038/s41388-021-01851-0

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