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:

KRT81 promotes metastasis of colorectal cancer by acting as a protein scaffold for ezrin

Oncogene volume 45, pages 459–475 (2026)Cite this article

Subjects

Abstract

Metastasis to distant organs represents the most fatal prognostic factor for colorectal cancer (CRC). The distant metastasis of tumor cells results from the collaborative effort of multiple subcellular structures, with dynamic cytoskeletal remodeling underlying this entire process. Here, we found that knockdown of KRT81 expression (shKRT81) inhibited the proliferation, invasion, and migration, while ectopic overexpression of KRT81 enhanced the CRC cells migration. Furthermore, we identified a potential downstream effector of KRT81, ezrin, a member of the ezrin/radixin/moesin (ERM) protein family that regulates cell morphology and motility. Phenotypically, the shKRT81 attenuated ezrin protein expression and reduced the number and length of filopodia in CRC cells, which were restored when KRT81 was re-overexpressed. Mechanistically, KRT81 formed a complex with ezrin, and recruitment of ezrin to the membrane and phosphorylation at the Thr567 residue were significantly abolished in shKRT81 cells. Interestingly, we found that Myosin 1B (MYO1B) might provide the driving force for the recruitment of ezrin. Notably, combinatorial inhibition (shKRT81 + ezrin-specific inhibitor) exerted significantly greater suppression of CRC cell migration and invasion than either intervention alone. Consistently, KRT81 expression was increased in CRC, and relatively high expression of KRT81 was associated with a poor prognosis. In summary, we identified a novel regulatory axis that involves KRT81, MYO1B, and ezrin, which regulates filopodia formation and migration behavior in CRC. Therefore, KRT81 may serve as a therapeutic target for CRC.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: KRT81 expression is increased in CRC and correlated with a poor outcome.
Fig. 2: Ectopic overexpression of KRT81 enhances the migration ability of CRC cells.
Fig. 3: KRT81 knockdown inhibits the proliferation, migration, and invasion in CRC cells.
Fig. 4: KRT81 is involved in the filopodia formation mediated by ezrin.
Fig. 5: KRT81 regulates the activation of ezrin.
Fig. 6: MYO1B may provide mechanochemical force for the membrane recruitment of ezrin.
Fig. 7: Combinatorial inhibition of KRT81 and ezrin exerts superior suppression of migration and invasion in CRC cells.
Fig. 8: KRT81 promotes CRC metastasis in vivo.

Similar content being viewed by others

Data availability

All data associated with the current study are presented in the manuscript or Supplementary Data. Original materials are available from the corresponding author on rational request.

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467–80.

    Article  PubMed  Google Scholar 

  3. Cervantes A, Adam R, Rosello S, Arnold D, Normanno N, Taieb J, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:10–32.

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021;325:669–85.

    Article  PubMed  CAS  Google Scholar 

  6. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.

    Article  PubMed  CAS  Google Scholar 

  7. Bose D, Meric-Bernstam F, Hofstetter W, Reardon DA, Flaherty KT, Ellis LM. Vascular endothelial growth factor targeted therapy in the perioperative setting: implications for patient care. Lancet Oncol. 2010;11:373–82.

    Article  PubMed  CAS  Google Scholar 

  8. Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021;39:273–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Diaz LA, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23:659–70.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gerstberger S, Jiang Q, Ganesh K. Metastasis. Cell. 2023;186:1564–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Zhan Q, Liu B, Situ X, Luo Y, Fu T, Wang Y, et al. New insights into the correlations between circulating tumor cells and target organ metastasis. Signal Transduct Tar. 2023;8:465.

    Article  CAS  Google Scholar 

  12. Liu W, Chen S, Xie W, Wang Q, Luo Q, Huang M, et al. MCCC2 is a novel mediator between mitochondria and telomere and functions as an oncogene in colorectal cancer. Cell Mol Biol Lett. 2023;28:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Herrmann H, Bar H, Kreplak L, Strelkov SV, Aebi U. Intermediate filaments: from cell architecture to nanomechanics. Nat Rev Mol Cell Biol. 2007;8:562–73.

    Article  PubMed  CAS  Google Scholar 

  14. Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002;40:403–39.

    Article  PubMed  CAS  Google Scholar 

  15. Kang DS, Moriarty A, Wang YJ, Thomas A, Hao J, Unger BA, et al. Ectopic Expression of a Truncated Isoform of Hair Keratin 81 in Breast Cancer Alters Biophysical Characteristics to Promote Metastatic Propensity. Adv Sci (Weinh). 2024;11:e2300509.

    Article  PubMed  Google Scholar 

  16. Schweizer J, Bowden PE, Coulombe PA, Langbein L, Lane EB, Magin TM, et al. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006;174:169–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Karantza V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 2011;30:127–38.

    Article  PubMed  CAS  Google Scholar 

  18. Aebi U, Fowler WE, Rew P, Sun TT. The fibrillar substructure of keratin filaments unraveled. J Cell Biol. 1983;97:1131–43.

    Article  PubMed  CAS  Google Scholar 

  19. Herrmann H, Aebi U. Intermediate Filaments: Structure and Assembly. Cold Spring Harb Perspect Biol. 2016;8:a018242.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Werner S, Keller L, Pantel K. Epithelial keratins: Biology and implications as diagnostic markers for liquid biopsies. Mol Asp Med. 2020;72:100817.

    Article  Google Scholar 

  21. Trask DK, Band V, Zajchowski DA, Yaswen P, Suh T, Sager R. Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci USA. 1990;87:2319–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Huang WC, Jang TH, Tung SL, Yen TC, Chan SH, Wang LH. A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing beta5-integrin/c-met signaling pathway. J Exp Clin Cancer Res. 2019;38:89.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Le J, Fu Y, Han Q, Ma Y, Ji H, Wei X, et al. Transcriptome Analysis of the Inhibitory Effect of Sennoside A on the Metastasis of Hepatocellular Carcinoma Cells. Front Pharm. 2020;11:566099.

    Article  CAS  Google Scholar 

  25. Győrffy B. Integrated analysis of public datasets for the discovery and validation of survival-associated genes in solid tumors. Innovation. 2024;5:100625.

    PubMed  PubMed Central  Google Scholar 

  26. Barik GK, Sahay O, Paul D, Santra MK. Ezrin gone rogue in cancer progression and metastasis: An enticing therapeutic target. Biochimica Et Biophysica Acta-Rev Cancer. 2022;1877:188753.

    Article  CAS  Google Scholar 

  27. Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol. 2010;11:276–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Tran Quang C, Gautreau A, Arpin M, Treisman R. Ezrin function is required for ROCK-mediated fibroblast transformation by the Net and Dbl oncogenes. EMBO J. 2000;19:4565–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Xie L, Huang H, Zheng Z, Yang Q, Wang S, Chen Y, et al. MYO1B enhances colorectal cancer metastasis by promoting the F-actin rearrangement and focal adhesion assembly via RhoA/ROCK/FAK signaling. Ann Transl Med. 2021;9:1543.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Gautreau A, Louvard D, Arpin M. Morphogenic effects of ezrin require a phosphorylation-induced transition from oligomers to monomers at the plasma membrane. J Cell Biol. 2000;150:193–203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Pelaseyed T, Viswanatha R, Sauvanet C, Filter JJ, Goldberg ML, Bretscher A. Ezrin activation by LOK phosphorylation involves a PIP(2)-dependent wedge mechanism. Elife. 2017;6:e22759.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zaman R, Lombardo A, Sauvanet C, Viswanatha R, Awad V, Bonomo LE, et al. Effector-mediated ERM activation locally inhibits RhoA activity to shape the apical cell domain. J Cell Biol. 2021;220:e202007146.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Qiao J, Tan Y, Liu H, Yang B, Zhang Q, Liu Q, et al. Histone H3K18 and Ezrin Lactylation Promote Renal Dysfunction in Sepsis-Associated Acute Kidney Injury. Adv Sci (Weinh). 2024;11:e2307216.

    Article  PubMed  Google Scholar 

  34. Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med. 2004;10:175–81.

    Article  PubMed  CAS  Google Scholar 

  35. Gilbert S, Loranger A, Lavoie JN, Marceau N. Cytoskeleton keratin regulation of FasR signaling through modulation of actin/ezrin interplay at lipid rafts in hepatocytes. Apoptosis. 2012;17:880–94.

    Article  PubMed  CAS  Google Scholar 

  36. Wald FA, Oriolo AS, Casanova ML, Salas PJ. Intermediate filaments interact with dormant ezrin in intestinal epithelial cells. Mol Biol Cell. 2005;16:4096–107.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gao S, Li E, Cui L, Lu X, Meng L, Yuan H, et al. Sp1 and AP-1 Regulate Expression of the Human Gene VIL2 in Esophageal Carcinoma Cells. J Biol Chem. 2009;284:7995–8004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Brown L, Waseem A, Cruz IN, Szary J, Gunic E, Mannan T, et al. Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation. Oncogene. 2013;33:2363–74.

    Article  PubMed  Google Scholar 

  39. Zhang RR, Feng XT, Zhan MS, Huang C, Chen K, Tang XY, et al. Transcription Factor Sp1 Promotes the Expression of Porcine Gene. Int J Mol Sci. 2016;17:112.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wang N, Yang Y, Pang M, Du C, Chen Y, Li S, et al. MicroRNA-135a-5p Promotes the Functional Recovery of Spinal Cord Injury by Targeting SP1 and ROCK. Mol Ther Nucleic Acids. 2020;22:1063–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Kang S, Kim J, Park A, Koh M, Shin W, Park G, et al. TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity. Nat Commun. 2023;14:700.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lin J, Zhang X, Ge W, Duan Y, Zhang X, Zhang Y, et al. Rnd3 Ameliorates Diabetic Cardiac Microvascular Injury via Facilitating Trim40-Mediated Rock1 Ubiquitination. Diabetes. 2025;74:569–84.

    Article  PubMed  CAS  Google Scholar 

  43. Almeida CG, Yamada A, Tenza D, Louvard D, Raposo G, Coudrier E. Myosin 1b promotes the formation of post-Golgi carriers by regulating actin assembly and membrane remodelling at the trans-Golgi network. Nat Cell Biol. 2011;13:779–89.

    Article  PubMed  CAS  Google Scholar 

  44. Coudrier E, Almeida CG. Myosin 1 controls membrane shape by coupling F-Actin to membrane. Bioarchitecture. 2014;1:230–5.

    Article  Google Scholar 

  45. Liu X, Salokas K, Tamene F, Jiu Y, Weldatsadik RG, Öhman T, et al. An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nat Commun. 2018;9:1188.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Go CD, Knight JDR, Rajasekharan A, Rathod B, Hesketh GG, Abe KT, et al. A proximity-dependent biotinylation map of a human cell. Nature. 2021;595:120–4.

    Article  PubMed  CAS  Google Scholar 

  47. Dydensborg AB, Rose AAN, Wilson BJ, Grote D, Paquet M, Giguère V, et al. GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis. Oncogene. 2009;28:2634–42.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the support of the National Key Clinical Discipline in general.

Author information

Author notes

  1. Wenqing Xie

    Present address: International Cancer Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, China

  2. These authors contributed equally: Minghan Huang, Wenqing Xie, Meihua Wu.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Minghan Huang, Wenqing Xie, Meihua Wu, Zhimei Ou, Caibin Li, Wanjun Liu, Min Zhi & Daici Chen

  2. Guangdong Institute of Gastroenterology, Guangzhou, Guangdong, China

    Minghan Huang, Wenqing Xie, Meihua Wu, Zhimei Ou, Caibin Li, Wanjun Liu, Min Zhi & Daici Chen

  3. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

    Minghan Huang, Wenqing Xie, Meihua Wu, Zhimei Ou, Caibin Li, Wanjun Liu & Daici Chen

  4. State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China

    Shuhui Ji

  5. Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Min Zhi

Authors
  1. Minghan Huang
    View author publications

    Search author on:PubMed Google Scholar

  2. Wenqing Xie
    View author publications

    Search author on:PubMed Google Scholar

  3. Meihua Wu
    View author publications

    Search author on:PubMed Google Scholar

  4. Zhimei Ou
    View author publications

    Search author on:PubMed Google Scholar

  5. Caibin Li
    View author publications

    Search author on:PubMed Google Scholar

  6. Shuhui Ji
    View author publications

    Search author on:PubMed Google Scholar

  7. Wanjun Liu
    View author publications

    Search author on:PubMed Google Scholar

  8. Min Zhi
    View author publications

    Search author on:PubMed Google Scholar

  9. Daici Chen
    View author publications

    Search author on:PubMed Google Scholar

Contributions

DC, MH, WX, WL, and MZ provided the study concept and design. DC and MZ supervised this study. MH, WX, WL, and MW performed the experiments. MH, MW, ZO, and WL conducted data analysis, and MH visualized the experimental data. SJ and MH performed the mass spectrometry and data analysis. MH, WX, and WL conducted clinical data and sample collection. DC provided financial support. MH drafted the manuscript. DC, MH, WX, WL, MW, and CL reviewed and prepared the final manuscript. All authors edited and approved the final version of the manuscript.

Corresponding authors

Correspondence to Wanjun Liu, Min Zhi or Daici Chen.

Ethics declarations

Competing interests

This work was financially supported by the Natural Science Foundation of China (Grant No. 31970703), Natural Science Foundation of Guangdong Province (Grant No. 2025A1515010593 and 2022A1515012472). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. The animal experiments were approved by the Laboratory Animal Center of SYSU-SAH (approval no. IACUC-2023122702), and tumor sizes were within the requirements of the animal center (<2 cm). Our study involving human specimens was approved by the Institutional Ethics Committee of SYSU-SAH (approval no. 2022ZSLYEC-469). All specimens in the SYSU-SAH biobank were collected and deposited after obtaining written informed consent from participants. This was a retrospective analysis of anonymized data, as the authors had no access to identifiable personal information during the analysis. Therefore, the requirement for informed consent was waived to this study by the ethics committee in accordance with applicable guidelines and regulations.

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

Huang, M., Xie, W., Wu, M. et al. KRT81 promotes metastasis of colorectal cancer by acting as a protein scaffold for ezrin. Oncogene 45, 459–475 (2026). https://doi.org/10.1038/s41388-025-03665-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03665-w

Search

Advanced search

Quick links