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CBX3 accelerates the malignant progression of glioblastoma multiforme by stabilizing EGFR expression

Oncogene volume 41, pages 3051–3063 (2022)Cite this article

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Abstract

CBX3, also known as HP1γ, is a major isoform of heterochromatin protein 1, whose deregulation has been reported to promote the development of human cancers. However, the molecular mechanism of CBX3 in glioblastoma multiforme (GBM) are unclear. Our study reported the identification of CBX3 as a potential therapeutic target for GBM. Briefly, we found that, CBX3 is significantly upregulated in GBM and reduces patient survival. In addition, functional assays demonstrated that CBX3 significantly promote the proliferation, invasion and tumorigenesis of GBM cells in vitro and in vivo. Mechanistically, Erlotinib, a small molecule targeting epidermal growth factor receptor (EGFR) tyrosine kinase, was used to demonstrate that CBX3 direct the malignant progression of GBM are EGFR dependent. Previous studies have shown that PARK2(Parkin) and STUB1(Carboxy Terminus of Hsp70-Interacting Protein) are EGFR-specific E3 ligases. Notably, we verified that CBX3 directly suppressed PARK2 and STUB1 at the transcriptional level through its CD domain to reduce the ubiquitination of EGFR. Moreover, the CSD domain of CBX3 interacted with PARK2 and regulated its ubiquitination to further reduce its protein level. Collectively, these results revealed an unknown mechanism underlying the pathogenesis of GBM and confirmed that CBX3 is a promising therapeutic target.

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Fig. 1: High expression of CBX3 is an indicator of poor prognosis in patients with GBM.
Fig. 2: CBX3 is essential for the proliferation, tumor growth and invasion of GBM cells.
Fig. 3: CBX3 reduces the ubiquitination of EGFR to mediate the EGFR signaling pathway.
Fig. 4: CBX3 directly inhibits STUB1 and PARK2 through its CD domain.
Fig. 5: CBX3 regulates the stability of PARK2 through its CSD domain.
Fig. 6: PARK2 and STUB1 act as downstream targets of CBX3 to regulate the progression of GBM.

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References

  1. Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15:422–42.

    Article  CAS  PubMed  Google Scholar 

  2. Stathias V, Jermakowicz AM, Maloof ME, Forlin M, Walters W, Suter RK, et al. Drug and disease signature integration identifies synergistic combinations in glioblastoma. Nat Commun. 2018;9:5315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Investig. 2017;127:415–26.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zhao Y, He J, Li Y, Lv S, Cui H. NUSAP1 potentiates chemoresistance in glioblastoma through its SAP domain to stabilize ATR. Signal Transduct Target Ther. 2020;5:44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xuan F, Huang M, Liu W, Ding H, Yang L, Cui H. Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. Neuro-Oncol. 2016;18:819–29.

    Article  CAS  PubMed  Google Scholar 

  6. Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001;410:116–20.

    Article  CAS  PubMed  Google Scholar 

  7. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001;410:120–4.

    Article  CAS  PubMed  Google Scholar 

  8. Akaike Y, Kuwano Y, Nishida K, Kurokawa K, Kajita K, Kano S, et al. Homeodomain-interacting protein kinase 2 regulates DNA damage response through interacting with heterochromatin protein 1gamma. Oncogene. 2015;34:3463–73.

    Article  CAS  PubMed  Google Scholar 

  9. Dialynas GK, Vitalini MW, Wallrath LL. Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutat Res. 2008;647:13–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Choi JD, Lee JS. Interplay between epigenetics and genetics in cancer. Genomics Inform. 2013;11:164–73.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Caillier M, Thenot S, Tribollet V, Birot AM, Samarut J, Mey A. Role of the epigenetic regulator HP1gamma in the control of embryonic stem cell properties. PloS One. 2010;5:e15507.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Sridharan R, Gonzales-Cope M, Chronis C, Bonora G, McKee R, Huang C, et al. Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1gamma in reprogramming to pluripotency. Nat Cell Biol. 2013;15:872–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu M, Huang F, Zhang D, Ju J, Wu XB, Wang Y, et al. Heterochromatin protein HP1gamma promotes colorectal cancer progression and is regulated by miR-30a. Cancer Res. 2015;75:4593–604.

    Article  CAS  PubMed  Google Scholar 

  14. Alam H, Li N, Dhar SS, Wu SJ, Lv J, Chen K, et al. HP1gamma promotes lung adenocarcinoma by downregulating the transcription-repressive regulators NCOR2 and ZBTB7A. Cancer Res. 2018;78:3834–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhong X, Kan A, Zhang W, Zhou J, Zhang H, Chen J, et al. CBX3/HP1gamma promotes tumor proliferation and predicts poor survival in hepatocellular carcinoma. Aging. 2019;11:5483–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen LY, Cheng CS, Qu C, Wang P, Chen H, Meng ZQ, et al. CBX3 promotes proliferation and regulates glycolysis via suppressing FBP1 in pancreatic cancer. Biochemical Biophysical Res Commun. 2018;500:691–7.

    Article  CAS  Google Scholar 

  17. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313:144–7.

    Article  CAS  PubMed  Google Scholar 

  18. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  19. Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro-Oncol. 2014;16:viii14–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang T, Yang J, Xu J, Li J, Cao Z, Zhou L, et al. CHIP is a novel tumor suppressor in pancreatic cancer through targeting EGFR. Oncotarget. 2014;5:1969–86.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lin DC, Xu L, Chen Y, Yan H, Hazawa M, Doan N, et al. Genomic and functional analysis of the E3 ligase PARK2 in glioma. Cancer Res. 2015;75:1815–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell. 1999;4:1029–40.

    Article  CAS  PubMed  Google Scholar 

  24. Shao G, Wang R, Sun A, Wei J, Peng K, Dai Q, et al. The E3 ubiquitin ligase NEDD4 mediates cell migration signaling of EGFR in lung cancer cells. Mol Cancer. 2018;17:24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Chen CY, Jan CI, Lo JF, Yang SC, Chang YL, Pan SH, et al. Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR Ubiquitinylation and degradation. Cancer Res. 2013;73:4009–19.

    Article  CAS  PubMed  Google Scholar 

  26. Hou J, Deng Q, Zhou J, Zou J, Zhang Y, Tan P, et al. CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene. 2017;36:1134–44.

    Article  CAS  PubMed  Google Scholar 

  27. Zhao SP, Wang F, Yang M, Wang XY, Jin CL, Ji QK, et al. CBX3 promotes glioma U87 cell proliferation and predicts an unfavorable prognosis. J Neurooncol. 2019;145:35–48.

    Article  CAS  PubMed  Google Scholar 

  28. Wang S, Liu F, Wang Y, Fan W, Zhao H, Liu L, et al. Integrated analysis of 34 microarray datasets reveals CBX3 as a diagnostic and prognostic biomarker in glioblastoma. J Transl Med. 2019;17:179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Chang SC, Lai YC, Chen YC, Wang NK, Wang WS, Lai JI. CBX3/heterochromatin protein 1 gamma is significantly upregulated in patients with non-small cell lung cancer. Asia Pac J Clin Oncol. 2018;14:e283–e288.

    Article  PubMed  Google Scholar 

  30. Viotti J, Duplan E, Caillava C, Condat J, Goiran T, Giordano C, et al. Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity. Oncogene. 2014;33:1764–75.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ, et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci. 2011;108:16259–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

    Article  PubMed  Google Scholar 

  33. Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, et al. European association for neuro-oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18:e315–e329.

    Article  PubMed  Google Scholar 

  34. Furnari FB, Cloughesy TF, Cavenee WK, Mischel PS. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat Rev Cancer. 2015;15:302–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eskilsson E, Rosland GV, Solecki G, Wang Q, Harter PN, Graziani G, et al. EGFR heterogeneity and implications for therapeutic intervention in glioblastoma. Neuro Oncol. 2018;20:743–52.

    Article  CAS  PubMed  Google Scholar 

  36. Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R. Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res. 2008;14:957–60.

    Article  CAS  PubMed  Google Scholar 

  37. Karpel-Massler G, Schmidt U, Unterberg A, Halatsch ME. Therapeutic inhibition of the epidermal growth factor receptor in high-grade gliomas: where do we stand? Mol Cancer Res. 2009;7:1000–12.

    Article  CAS  PubMed  Google Scholar 

  38. Hegi ME, Diserens AC, Bady P, Kamoshima Y, Kouwenhoven MC, Delorenzi M, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib–a phase II trial. Mol Cancer Ther. 2011;10:1102–12.

    Article  CAS  PubMed  Google Scholar 

  39. Chakravarti A, Wang M, Robins HI, Lautenschlaeger T, Curran WJ, Brachman DG, et al. RTOG 0211: a phase 1/2 study of radiation therapy with concurrent gefitinib for newly diagnosed glioblastoma patients. Int J Radiat Oncol Biol Phys. 2013;85:1206–11.

    Article  CAS  PubMed  Google Scholar 

  40. Reardon DA, Wen PY, Mellinghoff IK. Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neuro Oncol. 2014;16:viii7–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129:829–48.

    Article  CAS  PubMed  Google Scholar 

  42. Wang F, Zhang L, Luo Y, Zhang Q, Zhang Y, Shao Y, et al. The LncRNA RP11-279C4.1 enhances the malignant behaviour of glioma cells and glioma stem-like cells by regulating the miR-1273g-3p/CBX3 axis. Mol Neurobiol. 2021;58:3362–73.

    Article  CAS  PubMed  Google Scholar 

  43. Cai H, Yu Y, Ni X, Li C, Hu Y, Wang J, et al. LncRNA LINC00998 inhibits the malignant glioma phenotype via the CBX3-mediated c-Met/Akt/mTOR axis. Cell Death Dis. 2020;11:1032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gao F, Du Y, Zhang Y, Ren D, Xu J, Chen D. Circ-EZH2 knockdown reverses DDAH1 and CBX3-mediated cell growth and invasion in glioma through miR-1265 sponge activity. Gene. 2020;726:144196.

    Article  CAS  PubMed  Google Scholar 

  45. Li Q, Yu D, Yu Z, Gao Q, Chen R, Zhou L, et al. TIPE3 promotes non-small cell lung cancer progression via the protein kinase B/extracellular signal-regulated kinase 1/2-glycogen synthase kinase 3beta-beta-catenin/Snail axis. Transl Lung Cancer Res. 2021;10:936–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bhuripanyo K, Wang Y, Liu X, Zhou L, Liu R, Duong D, et al. Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer. Sci Adv. 2018;4:e1701393.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Zhang Y, Dube C, Gibert M, Cruickshanks N, Wang B, Coughlan M, et al. The p53 pathway in glioblastoma. Cancers. 2018;10:297.

    Article  PubMed Central  CAS  Google Scholar 

  48. Wong SC, Kamarudin MNA, Naidu R. Anticancer mechanism of curcumin on human glioblastoma. Nutrients. 2021;13:950.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. England B, Huang T, Karsy M. Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. Tumour Biol. 2013;34:2063–74.

    Article  CAS  PubMed  Google Scholar 

  50. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guimaraes DP, Hainaut P. TP53: a key gene in human cancer. Biochimie. 2002;84:83–93.

    Article  CAS  PubMed  Google Scholar 

  52. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137:413–31.

    Article  CAS  PubMed  Google Scholar 

  53. Okorokov AL, Orlova EV. Structural biology of the p53 tumour suppressor. Curr Opin Struct Biol. 2009;19:197–202.

    Article  CAS  PubMed  Google Scholar 

  54. Weisz L, Oren M, Rotter V. Transcription regulation by mutant p53. Oncogene. 2007;26:2202–11.

    Article  CAS  PubMed  Google Scholar 

  55. da Costa CA, Sunyach C, Giaime E, West A, Corti O, Brice A, et al. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson’s disease. Nat Cell Biol. 2009;11:1370–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Sunico CR, Nakamura T, Rockenstein E, Mante M, Adame A, Chan SF, et al. S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson’s disease. Mol Neurodegener. 2013;8:29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Yeo CW, Ng FS, Chai C, Tan JM, Koh GR, Chong YK, et al. Parkin pathway activation mitigates glioma cell proliferation and predicts patient survival. Cancer Res. 2012;72:2543–53.

    Article  CAS  PubMed  Google Scholar 

  58. Maugeri G, D’Amico AG, Magro G, Salvatorelli L, Barbagallo GM, Saccone S, et al. Expression profile of parkin isoforms in human gliomas. Int J Oncol. 2015;47:1282–92.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful for the research platform provided by Southwest University, and thank all the participants who contributed to this work.

Funding

This research was supported by the Natural Science Foundation of Chongqing (cstc2019jcyj-zdxmX0033) and Chongqing Doctoral Research and Innovation Project (CYB21131).

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Authors and Affiliations

  1. State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400716, China

    Wen Peng, Hanghua Liang, Jianbin Hou, Xiaosong Hu, Feng Wang, Jiayi Zhang, Shengjun Geng & Hongjuan Cui

  2. Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China

    Wen Peng, Hanghua Liang, Jianbin Hou, Xiaosong Hu, Feng Wang, Jiayi Zhang, Shengjun Geng & Hongjuan Cui

  3. Department of Neurosurgery, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Shuang Shi, Jiacheng Zhong, Xiaochuan Sun & Dong Zhong

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Contributions

HC, DZ, and WP designed this study. WP and HC performed all the experimental work. WP, SS, JZ, HL, JH, XH, JZ, SG, FW, XS, DZ, and HC analyzed the experimental data. HC and WP wrote drafts of the main text and collated diagrams. All authors have read, revised, and approved the final manuscript.

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Correspondence to Dong Zhong or Hongjuan Cui.

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Peng, W., Shi, S., Zhong, J. et al. CBX3 accelerates the malignant progression of glioblastoma multiforme by stabilizing EGFR expression. Oncogene 41, 3051–3063 (2022). https://doi.org/10.1038/s41388-022-02296-9

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