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:

MAD2L1 is transcriptionally regulated by TEAD4 and promotes cell proliferation and migration in colorectal cancer

Cancer Gene Therapy volume 30, pages 727–737 (2023)Cite this article

Subjects

Abstract

The molecular mechanism of network regulation in the occurrence and development of colorectal cancer (CRC) has been constantly improved. Here, we investigated the biological effects of TEAD4-MAD2L1 axis on proliferation and metastasis of human CRC cells. This study revealed that the expressions of MAD2L1 and TEAD4 in CRC tissues and CRC cell lines were significantly higher than those in adjacent epithelial tissues and normal intestinal epithelial cell line NCM460, and their expressions were significantly positively correlated; Moreover, inhibiting the expression of MAD2L1 or TEAD4 can inhibit the proliferation and migration of CRC cells and promote apoptosis. In addition, the promoter region of MAD2L1 gene has a TEAD4 binding site (motif sequence), and the transcription of MAD2L1 is positively regulated by TEAD4 protein; The inhibition of promotion/migration and promotion of apoptosis of CRC cells by silencing TEAD4 can be saved by the high expression of MAD2L1. In conclusion, our study suggests that the transcription and expression of MAD2L1 is regulated by TEAD4, which further promotes the proliferation and migration of CRC cells in vitro and in vivo, and inhibits apoptosis. MAD2L1 and TEAD4 are potential biomarkers for colorectal cancer.

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: Up-regulated expression of MAD2L1 in CRC.
Fig. 2: Silence of MAD2L1 inhibited the proliferation, migration and promoted apoptosis of HCT116 and RKO cells.
Fig. 3: MAD2L1 promotes CRC cell proliferation in vivo.
Fig. 4: MAD2L1 is transcriptionally regulated by TEAD4.
Fig. 5: Silence of TEAD4 inhibited the proliferation, migration and promoted apoptosis of CRC cells.
Fig. 6: The expression of MAD2L1 reversed the cell function changes induced by si-TEAD4.

Similar content being viewed by others

Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

References

  1. Kuipers EJ, Grady WM, Lieberman D, Seufferlein T, Sung JJ, Boelens PG, et al. Colorectal cancer. Nat Rev Dis Primers. 2015;1:15065

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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 

  3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. Kastrinos F, Samadder NJ, Burt RW. Use of family history and genetic testing to determine risk of colorectal cancer. Gastroenterology. 2020;158:389–403.

    Article  CAS  PubMed  Google Scholar 

  6. Harada S, Morlote D. Molecular pathology of colorectal cancer. Adv Anat Pathol. 2020;27:20–6.

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–23.

    Article  CAS  PubMed  Google Scholar 

  9. May KM, Hardwick KG. The spindle checkpoint. J Cell Sci. 2006;119:4139–42.

    Article  CAS  PubMed  Google Scholar 

  10. Barford D. Structure, function and mechanism of the anaphase promoting complex (APC/C). Q Rev Biophys. 2011;44:153–90.

    Article  CAS  PubMed  Google Scholar 

  11. Baker DJ, Chen J, van Deursen JM. The mitotic checkpoint in cancer and aging: what have mice taught us. Curr Opin Cell Biol. 2005;17:583–9.

    Article  CAS  PubMed  Google Scholar 

  12. Pfleger CM, Salic A, Lee E, Kirschner MW. Inhibition of Cdh1-APC by the MAD2-related protein MAD2L2: A novel mechanism for regulating Cdh1. Genes Dev. 2001;15:1759–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bates M, Furlong F, Gallagher MF, Spillane CD, McCann A, O'Toole S, et al. Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer. Cancer Lett. 2020;469:11–21.

    Article  CAS  PubMed  Google Scholar 

  14. Yu H. Structural activation of Mad2 in the mitotic spindle checkpoint: the two-state Mad2 model versus the Mad2 template model. J Cell Biol. 2006;173:153–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gibault F, Sturbaut M, Bailly F, Melnyk P, Cotelle P. Targeting Transcriptional Enhanced Associate Domains (TEADs). J Med Chem. 2018;61:5057–72.

    Article  CAS  PubMed  Google Scholar 

  16. Tomikawa J, Takada S, Okamura K, Terao M, Ogata-Kawata H, Akutsu H, et al. Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening. Nucleic Acids Res. 2020;48:278–89.

    Article  CAS  PubMed  Google Scholar 

  17. He L, Yuan L, Sun Y, Wang P, Zhang H, Feng X, et al. Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression. Cancer Res. 2019;79:4399–411.

    Article  CAS  PubMed  Google Scholar 

  18. Figeac N, Mohamed AD, Sun C, Schonfelder M, Matallanas D, Garcia-Munoz A, et al. VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle. J Cell Sci. 2019;132(13):jcs225946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang L, Gao Y, Zhao X, Guo C, Wang X, Yang Y, et al. HOXD3 was negatively regulated by YY1 recruiting HDAC1 to suppress progression of hepatocellular carcinoma cells via ITGA2 pathway. Cell Prolif. 2020;53:e12835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li Q, Tong D, Guo C, Wu F, Li F, Wang X, et al. MicroRNA-145 suppresses gastric cancer progression by targeting Hu-antigen R. Am J Physiol Cell Physiol. 2020;318:C605–C14.

    Article  PubMed  Google Scholar 

  21. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018;174:1034–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Martinez-Jimenez F, Muinos F, Sentis I, Deu-Pons J, Reyes-Salazar I, Arnedo-Pac C, et al. A compendium of mutational cancer driver genes. Nat Rev Cancer. 2020;20:555–72.

    Article  CAS  PubMed  Google Scholar 

  23. Zhu XF, Yi M, He J, Tang W, Lu MY, Li T, et al. Pathological significance of MAD2L1 in breast cancer: An immunohistochemical study and meta analysis. Int J Clin Exp Pathol. 2017;10:9190–201.

    PubMed  PubMed Central  Google Scholar 

  24. Li J, He X, Wu X, Liu X, Huang Y, Gong Y. miR-139-5p inhibits lung adenocarcinoma cell proliferation, migration, and invasion by targeting MAD2L1. Comput Math Methods Med. 2020;2020:2953598.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Teixeira JH, Silva P, Faria J, Ferreira I, Duarte P, Delgado ML, et al. Clinicopathologic significance of BubR1 and Mad2 overexpression in oral cancer. Oral Dis. 2015;21:713–20.

    Article  CAS  PubMed  Google Scholar 

  26. Li Y, Bai W, Zhang J. MiR-200c-5p suppresses proliferation and metastasis of human hepatocellular carcinoma (HCC) via suppressing MAD2L1. Biomed Pharmacother.2017;92:1038–44.

    Article  CAS  PubMed  Google Scholar 

  27. Sun L, Li J, Yan B. Gene expression profiling analysis of osteosarcoma cell lines. Mol Med Rep. 2015;12:4266–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang Z, Katsaros D, Shen Y, Fu Y, Canuto EM, Benedetto C, et al. Biological and clinical significance of MAD2L1 and BUB1, genes frequently appearing in expression signatures for breast cancer prognosis. PLoS One. 2015;10:e0136246.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Wang F, He J, Du J, Zhang H, Shi H, et al. miR-30a-3p Targets MAD2L1 and regulates proliferation of gastric cancer cells. Onco Targets Ther. 2019;12:11313–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen M, Huang B, Zhu L, Chen K, Liu M, Zhong C. Structural and functional overview of TEAD4 in cancer biology. Onco Targets Ther. 2020;13:9865–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zhang W, Li J, Wu Y, Ge H, Song Y, Wang D, et al. TEAD4 overexpression promotes epithelial-mesenchymal transition and associates with aggressiveness and adverse prognosis in head neck squamous cell carcinoma. Cancer Cell Int. 2018;18:178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li J, Li Z, Wu Y, Wang Y, Wang D, Zhang W, et al. The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma. Cell Death Dis. 2019;10:603.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Key Laboratory of environment and genes related to diseases (Xi’an Jiaotong University) and the biomedical experimental center of Xi’an Jiaotong University for providing experimental sites and equipment. We also thank Mr. Xiaofei Wang from the large instrument-sharing center of Xi’an Jiaotong University for his help in flow analysis.

Funding

This work was financially supported by the Provincial Health Research Foundation in Shaanxi Province (2022E008), Projects of Xi’an Youth Talent Lift Program (095920221363), National Natural Science Foundation of China (81874192), the Natural Science Basic Research Plan in Shaanxi Province (2022JQ-980), the Key of Research and Development Plan in Shaanxi Province (2021SF-129).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, the First Affiliated Hospital of Xi’an Medical University, Xi’an, 710077, Shaanxi, China

    Qian Li, Hua Wen, Manli Cui & Mingxin Zhang

  2. Institute of Genetics and Development Biology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, China

    Dongdong Tong, Xintao Jing, Fang Li, Qiuyu Jiang, Jinyuan Zhang & Chen Huang

  3. Shaanxi University of Traditional Chinese Medicine, Xianyang, 712046, Shaanxi, China

    Peihan Ma & Mingxin Zhang

Authors
  1. Qian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongdong Tong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xintao Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peihan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiuyu Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hua Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manli Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chen Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mingxin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

QL, CH, and MZ conceived and designed the experiments. QL, DT, XJ, FL, PM, and HW performed the experiments and analyzed the data. MC, QJ, and JZ performed bioinformatics analysis. QL, DT, and MZ wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Manli Cui, Chen Huang or Mingxin Zhang.

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 (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

Li, Q., Tong, D., Jing, X. et al. MAD2L1 is transcriptionally regulated by TEAD4 and promotes cell proliferation and migration in colorectal cancer. Cancer Gene Ther 30, 727–737 (2023). https://doi.org/10.1038/s41417-022-00586-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00586-8

This article is cited by

Search

Advanced search

Quick links