Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression

Oncogene volume 41, pages 4877–4892 (2022)Cite this article

Subjects

Abstract

PTEN is frequently mutated in human cancers, which leads to the excessive activation of PI3K/AKT signaling and thus promotes tumorigenesis and drug resistance. Met1-linked ubiquitination (M1-Ubi) is also involved in cancer progression, but the mechanism is poorly defined. Here we find that HOIP, one important component of linear ubiquitin chain assembly complex (LUBAC), promotes prostate cancer (PCa) progression by enhancing AKT signaling in a PTEN-dependent manner. Mechanistically, PTEN is modified by M1-Ubi at two sites K144 and K197, which significantly inhibits PTEN phosphatase activity and thus accelerates PCa progression. More importantly, we identify that the high-frequency mutants PTENR173H and PTENR173C in PCa patients showed the enhanced level of M1-Ubi, which impairs PTEN function in inhibition of AKT phosphorylation and cell growth. We also find that HOIP depletion sensitizes PCa cells to therapeutic agents BKM120 and Enzalutamide. Furthermore, the clinical data analyses confirm that HOIP is upregulated and positively correlated with AKT activation in PCa patient specimen, which may promote PCa progression and increase the risk of PCa biochemical relapse. Together, our study reveals a key role of PTEN M1-Ubi in regulation of AKT activation and PCa progression, which may propose a new strategy for PCa therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: HOIP depletion suppresses PCa cell progression.
Fig. 2: HOIP contributes to the activation of AKT signaling pathway in a PTEN-dependent manner.
Fig. 3: LUBAC binds to PTEN.
Fig. 4: PTEN harbors M1-Ubi mediated by LUBAC.
Fig. 5: PTEN M1-Ubi suppresses its phosphatase activity.
Fig. 6: Cancer-associated PTEN mutants with high M1-Ubi interfere with PTEN function in the regulation of AKT signaling.
Fig. 7: Clinical impact of HOIP expression on PCa progression.

Similar content being viewed by others

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

References

  1. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.

    Article  CAS  PubMed  Google Scholar 

  2. Marsh DJ, Dahia PLM, Coulon V, Zheng ZM, Dorion-Bonnet F, Call KM, et al. Allelic imbalance, including deletion of PTEN/MMACI, at the Cowden disease locus on 10q22-23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation. Genes Chromosomes Cancer. 1998;21:61–9.

    Article  CAS  PubMed  Google Scholar 

  3. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16:64–7.

    Article  CAS  PubMed  Google Scholar 

  4. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.

    Article  CAS  PubMed  Google Scholar 

  5. Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19:547–62.

    Article  CAS  PubMed  Google Scholar 

  6. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280:1614–7.

    Article  CAS  PubMed  Google Scholar 

  7. Gu T, Zhang Z, Wang J, Guo J, Shen WH, Yin Y. CREB is a novel nuclear target of PTEN phosphatase. Cancer Res. 2011;71:2821–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shi Y, Wang J, Chandarlapaty S, Cross J, Thompson C, Rosen N, et al. PTEN is a protein tyrosine phosphatase for IRS1. Nat Struct Mol Biol. 2014;21:522–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, et al. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 2011;17:461–9.

    Article  PubMed  Google Scholar 

  10. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128:157–70.

    Article  CAS  PubMed  Google Scholar 

  11. Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science. 2013;341:395–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ge MK, Zhang N, Xia L, Zhang C, Dong SS, Li ZM, et al. FBXO22 degrades nuclear PTEN to promote tumorigenesis. Nat Commun. 2020;11:1720.

  13. Vazquez F, Ramaswamy S, Nakamura N, Sellers WR. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol. 2000;20:5010–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Torres J, Pulido R. The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C-terminus: implications for PTEN stability to proteasome-mediated degradation. Protein Modules Cell Signal. 2001;318:350–60.

    CAS  Google Scholar 

  15. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell. 2007;128:129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, et al. WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol. 2011;13:728–33.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dou J, Zhang H, Chen R, Shu Z, Yuan H, Zhao X, et al. SUMOylation modulates the LIN28A-let-7 signaling pathway in response to cellular stresses in cancer cells. Mol Oncol. 2020;14:2288–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huang J, Yan J, Zhang J, Zhu S, Wang Y, Shi T, et al. SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. Nat Commun. 2012;3:911.

    Article  PubMed  Google Scholar 

  19. Okumura K, Mendoza M, Bachoo RM, DePinho RA, Cavenee WK, Furnari FB. PCAF modulates PTEN activity. J Biol Chem. 2006;281:26562–8.

    Article  CAS  PubMed  Google Scholar 

  20. Xie P, Peng Z, Chen Y, Li H, Du M, Tan Y, et al. Neddylation of PTEN regulates its nuclear import and promotes tumor development. Cell Res. 2021;31:291–311.

    Article  CAS  PubMed  Google Scholar 

  21. Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006;25:4877–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature. 2011;471:637–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011;471:591–6.

    Article  CAS  PubMed  Google Scholar 

  24. Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 2009;11:123–32.

    Article  CAS  PubMed  Google Scholar 

  25. de Almagro MC, Goncharov T, Newton K, Vucic D. Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. Cell Death Dis. 2015;6:e1800.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Goto E, Tokunaga F. Decreased linear ubiquitination of NEMO and FADD on apoptosis with caspase-mediated cleavage of HOIP. Biochem Biophys Res Commun. 2017;485:152–9.

    Article  CAS  PubMed  Google Scholar 

  27. Noad J, von der Malsburg A, Pathe C, Michel MA, Komander D, Randow F. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-kappaB. Nat Microbiol. 2017;2:17063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Inn KS, Gack MU, Tokunaga F, Shi M, Wong LY, Iwai K, et al. Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction. Mol Cell. 2011;41:354–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rivkin E, Almeida SM, Ceccarelli DF, Juang YC, MacLean TA, Srikumar T, et al. The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis. Nature. 2013;498:318–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sasaki Y, Sano S, Nakahara M, Murata S, Kometani K, Aiba Y, et al. Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. EMBO J. 2013;32:2463–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M, et al. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell. 2012;46:746–58.

    Article  CAS  PubMed  Google Scholar 

  32. Peltzer N, Rieser E, Taraborrelli L, Draber P, Darding M, Pernaute B, et al. HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell Rep. 2014;9:153–65.

    Article  CAS  PubMed  Google Scholar 

  33. Dittmar G, Winklhofer KF. Linear ubiquitin chains: cellular functions and strategies for detection and quantification. Front Chem. 2019;7:915.

    Article  CAS  PubMed  Google Scholar 

  34. Fu Y, Wang H, Dai H, Zhu Q, Cui CP, Sun X, et al. OTULIN allies with LUBAC to govern angiogenesis by editing ALK1 linear polyubiquitin. Mol Cell. 2021;81:3187–204.e.

    Article  CAS  PubMed  Google Scholar 

  35. van Well EM, Bader V, Patra M, Sanchez-Vicente A, Meschede J, Furthmann N, et al. A protein quality control pathway regulated by linear ubiquitination. EMBO J. 2019;38:e100730.

  36. Zhu J, Zhao C, Kharman-Biz A, Zhuang T, Jonsson P, Liang N, et al. The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor alpha and modulates estrogen-stimulated breast cancer cell proliferation. Oncogene. 2014;33:4340–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kharman-Biz A, Gao H, Ghiasvand R, Haldosen LA, Zendehdel K. Expression of the three components of linear ubiquitin assembly complex in breast cancer. PLoS ONE. 2018;13:e0197183.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Guo J, Liu X, Wang M. miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer. Biochem Biophys Res Commun. 2015;464:1302–8.

    Article  CAS  PubMed  Google Scholar 

  39. He L, Ingram A, Rybak AP, Tang D. Shank-interacting protein-like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells. J Clin Investig. 2010;120:2094–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang HL, Zhao X, Guo YM, Chen R, He JF, Li L, et al. Hypoxia regulates overall mRNA homeostasis by inducing Met(1)-linked linear ubiquitination of AGO2 in cancer cells. Nat Commun. 2021;12:5416.

  41. Zhang Y, Kwok-Shing NgP, Kucherlapati M, Chen F, Liu Y, Tsang YH, et al. A pan-cancer proteogenomic atlas of PI3K/AKT/mTOR pathway alterations. Cancer Cell. 2017;31:820–32.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 2009;136:1098–109.

    Article  CAS  PubMed  Google Scholar 

  43. Sakamoto H, Egashira S, Saito N, Kirisako T, Miller S, Sasaki Y, et al. Gliotoxin suppresses NF-kappaB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). ACS Chem Biol. 2015;10:675–81.

    Article  CAS  PubMed  Google Scholar 

  44. Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, et al. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013;50:818–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Takiuchi T, Nakagawa T, Tamiya H, Fujita H, Sasaki Y, Saeki Y, et al. Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. Genes Cells. 2014;19:254–72.

    Article  CAS  PubMed  Google Scholar 

  46. Schaeffer V, Akutsu M, Olma MH, Gomes LC, Kawasaki M, Dikic I. Binding of OTULIN to the PUB domain of HOIP controls NF-kappaB signaling. Mol Cell. 2014;54:349–61.

    Article  CAS  PubMed  Google Scholar 

  47. Kliza K, Taumer C, Pinzuti I, Franz-Wachtel M, Kunzelmann S, Stieglitz B, et al. Internally tagged ubiquitin: a tool to identify linear polyubiquitin-modified proteins by mass spectrometry. Nat Methods. 2017;14:504–12.

    Article  CAS  PubMed  Google Scholar 

  48. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15:222–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wong CW, Or PMY, Wang Y, Li L, Li J, Yan M, et al. Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly. Autism Res. 2018;11:1098–109.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Singh G, Odriozola L, Guan H, Kennedy CR, Chan AM. Characterization of a novel PTEN mutation in MDA-MB-453 breast carcinoma cell line. BMC Cancer. 2011;11:490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang JM, Schiapparelli P, Nguyen HN, Igarashi A, Zhang Q, Abbadi S, et al. Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene. 2017;36:3673–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu PJ, Gao W, Su M, Nice EC, Zhang WH, Lin J, et al. Adaptive mechanisms of tumor therapy resistance driven by tumor microenvironment. Front Cell Dev Biol. 2021;9:641469.

  53. Vanhaesebroeck B, Perry MWD, Brown JR, Andre F, Okkenhaug K. PI3K inhibitors are finally coming of age. Nat Rev Drug Discov. 2021;20:741–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, et al. Identification and characterization of NVP-BKM120, an orally available Pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11:317–28.

    Article  CAS  PubMed  Google Scholar 

  55. Armstrong AJ, Halabi S, Healy P, Alumkal JJ, Winters C, Kephart J, et al. Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. Eur J Cancer. 2017;81:228–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Iwai K, Fujita H, Sasaki Y. Linear ubiquitin chains: NF-kappaB signalling, cell death and beyond. Nat Rev Mol Cell Biol. 2014;15:503–8.

    Article  CAS  PubMed  Google Scholar 

  57. Wang W, Li MQ, Ponnusamy S, Chi YY, Xue JY, Fahmy B, et al. ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/beta-catenin activation to enhance drug resistance in breast cancers. Nat Commun. 2020;11:3965.

  58. Zuo Y, Feng Q, Jin L, Huang F, Miao Y, Liu J, et al. Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling. Nat Commun. 2020;11:1146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Thompson HG, Harris JW, Lin L, Brody JP. Identification of the protein Zibra, its genomic organization, regulation, and expression in breast cancer cells. Exp Cell Res. 2004;295:448–59.

    Article  CAS  PubMed  Google Scholar 

  60. Qiu P, Xu TJ, Lu XD, Yang W, Zhang YB, Xu GM. MicroRNA-378 regulates cell proliferation and migration by repressing RNF31 in pituitary adenoma. Oncol Lett. 2018;15:789–94.

    PubMed  Google Scholar 

  61. Zhu J, Zhao C, Zhuang T, Jonsson P, Sinha I, Williams C, et al. RING finger protein 31 promotes p53 degradation in breast cancer cells. Oncogene. 2016;35:1955–64.

    Article  CAS  PubMed  Google Scholar 

  62. Serebriiskii IG, Pavlov V, Tricarico R, Andrianov G, Nicolas E, Parker MI, et al. Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers. Nat Commun. 2022;13:1618.

  63. Smith IN, Briggs JM. Structural mutation analysis of PTEN and its genotype-phenotype correlations in endometriosis and cancer. Proteins Struct Funct Bioinform. 2016;84:1625–43.

    Article  CAS  Google Scholar 

  64. Deng R, Guo Y, Li L, He J, Qiang Z, Zhang H, et al. BAP1 suppresses prostate cancer progression by deubiquitinating and stabilizing PTEN. Mol Oncol. 2021;15:279–98.

    Article  CAS  PubMed  Google Scholar 

  65. Cheng C, Ru P, Geng F, Liu J, Yoo JY, Wu X, et al. Glucose-mediated N-glycosylation of SCAP is essential for SREBP-1 activation and tumor growth. Cancer Cell. 2015;28:569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by grants from China’s National Key R&D Programmes (NKP) (No. 2019YFE0110600), the National Natural Science Foundation of China (81630075, 82103082, 81721004, 81902866, 82002712, 81972585) and Shanghai Science and Technology Commission (20JC1410100).

Author information

Author notes

  1. These authors contributed equally: Yanmin Guo, Jianfeng He, Hailong Zhang, Ran Chen.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

    Yanmin Guo, Jianfeng He, Hailong Zhang, Ran Chen, Lian Li, Xiaojia Liu, Caihu Huang, Zhe Qiang, Zihan Zhou, Yanli Wang, Jian Huang, Xian Zhao & Jianxiu Yu

  2. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

    Junke Zheng

  3. State Key Laboratory of Oncogenes and Related Genes, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

    Guo-Qiang Chen

Authors
  1. Yanmin Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianfeng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hailong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ran Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaojia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Caihu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhe Qiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zihan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Junke Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Guo-Qiang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jianxiu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.Y., Y.G., and H.Z. conceived and designed the study. Y.G., J.H., H.Z., and R.C. performed most of the experiments. L.L., X.L., C.H., Z.Q., Z.Z., Y.W., J.H., and X.Z. helped with experiments and provided technical support. J.H., X.Z., J.Z., and G.C. offered some constructive suggestions. J.Y., Y.G., J.H., and H.Z. analyzed the data. J.Y. and Y.G. wrote the paper.

Corresponding author

Correspondence to Jianxiu Yu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, Y., He, J., Zhang, H. et al. Linear ubiquitination of PTEN impairs its function to promote prostate cancer progression. Oncogene 41, 4877–4892 (2022). https://doi.org/10.1038/s41388-022-02485-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02485-6

This article is cited by

Search

Advanced search

Quick links