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:

Downregulation of TEX11 promotes S-Phase progression and proliferation in colorectal cancer cells through the FOXO3a/COP1/c-Jun/p21 axis

Oncogene volume 41, pages 5133–5145 (2022)Cite this article

Subjects

Abstract

Colorectal cancer (CRC) is the most common digestive tract malignancy, attributing to approximately 9.4% of global cancer-related deaths. However, the pathogenesis of CRC is poorly understood. The testis-expressed 11 (TEX11) gene is located on the X chromosome and is required for spermatogenesis, and is reported might serve as a biomarker for early onset CRC according to database analysis. However, the role played by TEX11 in cancer progression remains to be investigated. In this study, we show that TEX11 expression is significantly downregulated in CRC cell lines and clinical CRC tissue samples, and TEX11 expression correlates with poor prognosis in CRC patients. We further demonstrate that TEX11 can significantly inhibit the proliferative capacity of CRC cells in vitro and in vivo. Mechanistically, we demonstrate that TEX11 promotes transcription of COP1 by upregulating FOXO3a expression. This enhanced COP1 expression subsequently accelerates the degradation of the negative transcriptional regulator c-Jun, which, in turn, enhances p21 transcription inhibiting CRC cell cycle progression and proliferation. Overall, our findings suggest that TEX11 may be a valuable therapeutic target for the treatment of CRC.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: TEX11 expression is downregulated in human CRC tissue, correlating with the poor prognosis of patients.
Fig. 2: Heterologous expression of TEX11 significantly inhibits the proliferative capacity of CRC cells in vitro.
Fig. 3: Heterologous expression of TEX11 significantly inhibited the proliferative capacity of CRC cells in vivo.
Fig. 4: TEX11 inhibits CRC cell proliferation by promoting cell cycle arrest via the upregulation of p21 expression.
Fig. 5: TEX11 inhibits the transcription of p21 by downregulating the expression of c-Jun.
Fig. 6: TEX11 promotes the degradation of c-Jun protein by upregulating the expression of COP1.
Fig. 7: TEX11 promotes the transcription of COP1 by upregulating the expression of FOXO3a.
Fig. 8: Overexpression of TEX11 partially suppresses tumor growth in xenograft of colorectal cancer cells.
Fig. 9: Protein expression correlation analysis of the TEX11/FOXO3a/COP1/C-Jun/p21 pathway.
Fig. 10: Mechanistic diagram of the inhibition of colorectal cancer cell proliferation by TEX11 through the FOXO3a/COP1/c-Jun/p21 axis.

Similar content being viewed by others

Data availability

The dataset used during the study is available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Boeding JRE, Ramphal W, Crolla R, Boonman-de Winter LJM, Gobardhan PD, Schreinemakers JMJ. Ileus caused by obstructing colorectal cancer-impact on long-term survival. Int J Colorectal Dis. 2018;33:1393–400.

    Article  PubMed  Google Scholar 

  3. Akgul O, Cetinkaya E, Ersoz S, Tez M. Role of surgery in colorectal cancer liver metastases. World J Gastroenterol. 2014;20:6113–22.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020;5:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marmol I, Sanchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi MJ. Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017;18:197.

  6. Garciaa R, Aguilera A, Contreras-Esquivel JC, Rodriguez R, Aguilar CN. Extraction of condensed tannins from Mexican plant sources. Z Naturforsch C J Biosci. 2008;63:17–20.

    Article  PubMed  Google Scholar 

  7. Tuttelmann F, Ruckert C, Ropke A. Disorders of spermatogenesis: Perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genet. 2018;30:12–20.

    PubMed  PubMed Central  Google Scholar 

  8. Guiraldelli MF, Felberg A, Almeida LP, Parikh A, de Castro RO, Pezza RJ. SHOC1 is a ERCC4-(HhH)2-like protein, integral to the formation of crossover recombination intermediates during mammalian meiosis. PLoS Genet. 2018;14:e1007381.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dapper AL, Payseur BA. Molecular evolution of the meiotic recombination pathway in mammals. Evolution. 2019;73:2368–89.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Luo T, Wu S, Shen X, Li L. Network cluster analysis of protein-protein interaction network identified biomarker for early onset colorectal cancer. Mol Biol Rep. 2013;40:6561–8.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Y, Chen F, Chandrashekar DS, Varambally S, Creighton CJ. Proteogenomic characterization of 2002 human cancers reveals pan-cancer molecular subtypes and associated pathways. Nat Commun. 2022;13:2669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen F, Chandrashekar DS, Scheurer ME, Varambally S, Creighton CJ. Global molecular alterations involving recurrence or progression of pediatric brain tumors. Neoplasia. 2022;24:22–33.

    Article  PubMed  Google Scholar 

  13. Blanchard JM. Cyclin A2 transcriptional regulation: modulation of cell cycle control at the G1/S transition by peripheral cues. Biochem Pharm. 2000;60:1179–84.

    Article  CAS  PubMed  Google Scholar 

  14. Hume S, Dianov GL, Ramadan K. A unified model for the G1/S cell cycle transition. Nucl. Acids Res. 2020;48:12483–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. El-Deiry WS. p21(WAF1) Mediates Cell-Cycle Inhibition, Relevant to Cancer Suppression and Therapy. Cancer Res. 2016;76:5189–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Messeguer X, Escudero R, Farre D, Nunez O, Martinez J, Alba MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002;18:333–4.

    Article  CAS  PubMed  Google Scholar 

  17. Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31:3651–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fornes O, Castro-Mondragon JA, Khan A, van der Lee R, Zhang X, Richmond PA, et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res. 2020;48:D87–D92.

    CAS  PubMed  Google Scholar 

  19. Wang CH, Tsao YP, Chen HJ, Chen HL, Wang HW, Chen SL. Transcriptional repression of p21((Waf1/Cip1/Sdi1)) gene by c-jun through Sp1 site. Biochem Biophys Res Commun. 2000;270:303–10.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng JM, Yao MR, Zhu Q, Wu XY, Zhou J, Tan WL, et al. Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells. J Biol Regul Homeost Agents. 2015;29:85–92.

    CAS  PubMed  Google Scholar 

  21. Hershko A. The ubiquitin pathway for protein degradation. Trends Biochem Sci. 1991;16:265–8.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Le WD. Autophagy and Ubiquitin-Proteasome System. Adv Exp Med Biol. 2019;1206:527–50.

    Article  CAS  PubMed  Google Scholar 

  23. Wang ZB, Liu YQ, Cui YF. Pathways to caspase activation. Cell Biol Int. 2005;29:489–96.

    Article  CAS  PubMed  Google Scholar 

  24. Csizmok V, Montecchio M, Lin H, Tyers M, Sunnerhagen M, Forman-Kay JD. Multivalent Interactions with Fbw7 and Pin1 Facilitate Recognition of c-Jun by the SCF(Fbw7) Ubiquitin Ligase. Structure. 2018;26:28–39.e22.

    Article  CAS  PubMed  Google Scholar 

  25. Migliorini D, Bogaerts S, Defever D, Vyas R, Denecker G, Radaelli E, et al. Cop1 constitutively regulates c-Jun protein stability and functions as a tumor suppressor in mice. J Clin Invest. 2011;121:1329–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gao B, Lee SM, Fang D. The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells. J Biol Chem. 2006;281:29711–8.

    Article  CAS  PubMed  Google Scholar 

  27. Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome-wide recombination rates in mouse. EMBO Mol Med. 2015;7:1198–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yatsenko AN, Georgiadis AP, Ropke A, Berman AJ, Jaffe T, Olszewska M, et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. 2015;372:2097–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zheng K, Yang F, Wang PJ. Regulation of male fertility by X-linked genes. J Androl. 2010;31:79–85.

    Article  CAS  PubMed  Google Scholar 

  30. Karimian A, Ahmadi Y, Yousefi B. Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage. DNA Repair (Amst). 2016;42:63–71.

    Article  CAS  Google Scholar 

  31. Shamloo B. Usluer S p21 in Cancer Research. Cancers (Basel). 2019;11:1178.

  32. Song Y, Liu Y, Pan S, Xie S, Wang ZW, Zhu X. Role of the COP1 protein in cancer development and therapy. Semin Cancer Biol. 2020;67:43–52.

    Article  CAS  PubMed  Google Scholar 

  33. Fasano C, Disciglio V, Bertora S, Lepore Signorile M, Simone C. FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response. Cells. 2019;8:1110.

  34. Nho RS, Hergert P. FoxO3a and disease progression. World J Biol Chem. 2014;5:346–54.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wang F, Marshall CB, Ikura M. Forkhead followed by disordered tail: The intrinsically disordered regions of FOXO3a. Intrinsically Disord Proteins. 2015;3:e1056906.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nestal de Moraes G, Bella L, Zona S, Burton MJ, Lam EW. Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance. Curr Drug Targets. 2016;17:164–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17:104.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chacko L, Macaron C, Burke CA. Colorectal cancer screening and prevention in women. Dig Dis Sci. 2015;60:698–710.

    Article  PubMed  Google Scholar 

  39. Koo JH, Leong RW. Sex differences in epidemiological, clinical and pathological characteristics of colorectal cancer. J Gastroenterol Hepatol. 2010;25:33–42.

    Article  PubMed  Google Scholar 

  40. Ray AL, Nofchissey RA, Khan MA, Reidy MA, Lerner MR, Wu X, et al. The role of sex in the innate and adaptive immune environment of metastatic colorectal cancer. Br J Cancer. 2020;123:624–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gausman V, Dornblaser D, Anand S, Hayes RB, O’Connell K, Du M, et al. Risk Factors Associated With Early-Onset Colorectal Cancer. Clin Gastroenterol Hepatol. 2020;18:2752–9.e2752.

    Article  PubMed  Google Scholar 

  42. Lukashev AN, Zamyatnin AA Jr. Viral Vectors for Gene Therapy: Current State and Clinical Perspectives. Biochem (Mosc). 2016;81:700–8.

    Article  CAS  Google Scholar 

  43. Watanabe M, Nishikawaji Y, Kawakami H, Kosai KI. Adenovirus Biology, Recombinant Adenovirus, and Adenovirus Usage in Gene Therapy. Viruses. 2021;13:2502.

  44. Li H, Zhang N, Jiao X, Wang C, Sun W, He Y, et al. Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3beta. Clin Transl Med. 2021;11:e602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jin H, Sun W, Zhang Y, Yan H, Liufu H, Wang S, et al. MicroRNA-411 Downregulation Enhances Tumor Growth by Upregulating MLLT11 Expression in Human Bladder Cancer. Mol Ther Nucleic Acids. 2018;11:312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Bioinformatics results described here are based on data from the TCGA research network (http://cancergenome.nih.gov/). We thank all participants, specimen donors, and research groups who participated in the creation of the TCGA CRC cancer dataset. This work was partially supported by the Key Project of Science and Technology Innovation Team of Zhejiang Province (2013TD10), Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A), Wenzhou Science & Technology Bureau (Y20180857), and Wenzhou Medical University (89219018).

Author information

Author notes

  1. These authors contributed equally: Xiaodong Zhang, Fangyu Hu, Baiwang Zhu.

Authors and Affiliations

  1. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Xiaodong Zhang, Baiwang Zhu & Yifei Pan

  2. Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Fangyu Hu, Xueli Jiao, Yun Li, Shuang Wu, Ganglin Ren, Hongyan Li & Lingling Zhao

  3. The Second Affiliated Hospital &Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China

    Jizhen Li & Qipeng Xie

Authors
  1. Xiaodong Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Fangyu Hu
    View author publications

    Search author on:PubMed Google Scholar

  3. Baiwang Zhu
    View author publications

    Search author on:PubMed Google Scholar

  4. Xueli Jiao
    View author publications

    Search author on:PubMed Google Scholar

  5. Yun Li
    View author publications

    Search author on:PubMed Google Scholar

  6. Shuang Wu
    View author publications

    Search author on:PubMed Google Scholar

  7. Ganglin Ren
    View author publications

    Search author on:PubMed Google Scholar

  8. Jizhen Li
    View author publications

    Search author on:PubMed Google Scholar

  9. Qipeng Xie
    View author publications

    Search author on:PubMed Google Scholar

  10. Yifei Pan
    View author publications

    Search author on:PubMed Google Scholar

  11. Hongyan Li
    View author publications

    Search author on:PubMed Google Scholar

  12. Lingling Zhao
    View author publications

    Search author on:PubMed Google Scholar

Contributions

LZ, HL, XZ, and YP conceived and designed the study. XZ, XJ, FH, YL, SW, BZ, and GR detected the biological functions of cells, performed the RT-qPCR assays, and conducted statistical analyses. JL and LZ performed animal experiments. XZ and QX collected and analyzed clinical samples. HL, LZ, and XZ drafted the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Yifei Pan, Hongyan Li or Lingling Zhao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

All experiments related to clinical specimens were approved by the ethics committee of Wenzhou Medical University (YS2019-170). All animal experiments were performed in accordance with the management regulations of the Experimental Animal Ethics Committee of Wenzhou Medical University (WYYY-AEC-YS-2022-0260).

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 (e.g. a society or other partner) 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

Zhang, X., Hu, F., Zhu, B. et al. Downregulation of TEX11 promotes S-Phase progression and proliferation in colorectal cancer cells through the FOXO3a/COP1/c-Jun/p21 axis. Oncogene 41, 5133–5145 (2022). https://doi.org/10.1038/s41388-022-02490-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-022-02490-9

This article is cited by

Search

Advanced search

Quick links