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:

CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis

Oncogene volume 44, pages 909–926 (2025)Cite this article

Subjects

Abstract

Chromobox homolog 2 (CBX2), a component of the polycomb repressive complex 1, is overexpressed in various cancers, but its specific role in colorectal cancer (CRC) is not fully understood. This study aimed to characterize the functional and regulatory roles of CBX2 in CRC. Tissue microarray analysis revealed the elevated CBX2 levels in tumor compared to adjacent normal tissues, which is significantly correlated with poor prognosis. Gain and loss of function studies demonstrated that CBX2 significantly promoted CRC progression and chemoresistance in cell lines, patient-derived CRC organoids and xenografts. In the AOM/DSS mouse model, treatment with the innovatively-developed cy5-PBAE/siCBX2 nanoparticle significantly reduced tumor aggressiveness. Mechanistic studies unveiled that the transcription factor RUNX1 is the positive regulator of CBX2. RNA-seq, ATAC-seq and CUT & RUN results indicated CBX2 knockdown induced epigenetic changes, especially alterations in chromatin accessibility. Moreover, we further identified MAP4K1 as a target gene of RUNX1-CBX2, with significant clinical and prognostic relevance in CRC. Collectively, these findings suggest the pivotal role of RUNX1-CBX2-MAP4K1 axis in CRC progression and underscore CBX2 as a promising biomarker and therapeutic target.

The regulatory function of CBX2 on chromatin accessibility and the role of the RUNX1-CBX2-MAP4K1-pERK axis in the progression of colorectal cancer.

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: CBX2 is a novel biomarker and prognostic indicator in colorectal cancer (CRC).
Fig. 2: CBX2 contributed to the proliferation of CRC in vitro.
Fig. 3: CBX2 promotes the CRC progression in patient-derived organoids (PDOs) and in vivo.
Fig. 4: CBX2 increases the chemoresistance of CRC in vitro and in vivo.
Fig. 5: RUNX1 activation enhances CBX2 expression and CRC progression.
Fig. 6: CBX2 depletion changes chromatin accessibility and transcriptome in CRC cells.
Fig. 7: MAP4K1 is the key downstream functional gene of CBX2 in CRC.
Fig. 8: PBAE/siCBX2 nanocomplex suppressed colorectal tumor growth in vivo.

Similar content being viewed by others

Data availability

All data associated with this study were present in the paper or the additional files. All datasets or information generated in this study are available upon reasonable request from the corresponding authors. The sequencing datasets have been deposited in the Gene Expression Omnibus (GEO) database as GSE284547.

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.

    Article  PubMed  Google Scholar 

  2. Melina A, Christian CA, Rachel EN, Jerome V, Edward LG, Katherine AM, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159:335–49.e15.

    Google Scholar 

  3. Gholamreza R, Fatemeh G-K, Reza M. Colorectal cancer: epidemiology, risk factors, and prevention. Cancers. 2024;16:1530.

    Google Scholar 

  4. Junyi X, Dongying G, Shuwei L, Sangni Q, Yifei C, Wei S, et al. Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment. Nat Commun. 2024;15:3042.

    Google Scholar 

  5. Ree AH, Šaltytė Benth J, Hamre HM, Kersten C, Hofsli E, Guren MG, et al. First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial. Br J Cancer. 2024;130:1921–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Marwan F, Chongkai W, Jaideep S, Jian Y, Colt E, Xiaochen L. Immunotherapy response in microsatellite stable metastatic colorectal cancer is influenced by site of metastases. Eur J Cancer. 2023;196:113437.

  7. Rona Y, Nataliya VU, Meredith SP, Tanios SB-S, Minal B, Joel S, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRASG12C-mutated metastatic colorectal cancer. Cancer Discov. 2024;14:982–93.

    Google Scholar 

  8. Lindsay WB, Donald SB, Vu TN, Philip R, Tomomi MY, Elizabeth RW, et al. Novel chromobox 2 inhibitory peptide decreases tumor progression. Expert Opin Ther Targets. 2023;27:361–71.

    Google Scholar 

  9. Nunzio DG, Antonella DC, Ning Qing L, Lidio C, Carmela DA, Guglielmo B, et al. CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway. Mol Cancer. 2022;21:125.

    Google Scholar 

  10. Glancy E, Wang C, Tuck E, Healy E, Amato S, Neikes HK, et al. PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1. Mol Cell. 2023;83:1393–411.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Susan LK, Matthew MM, Baymaz HI, Lisa VV, Ino DK, Alexandra S, et al. The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation. Nat Struct Mol Biol. 2016;23:682–90.

    Google Scholar 

  12. Wunderlich Z, Bragdon MDJ, Vincent BJ, White JA, Estrada J, DePace AH. Non-canonical PRC1.1 targets active genes independent of H3K27me3 and is essential for leukemogenesis. Cell Rep. 2016;14:3030.

    CAS  PubMed  Google Scholar 

  13. Anke S, Maarten VL. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–56.

    Google Scholar 

  14. He Z, Yongfu X, Zuoliang L, Songlin H, Tong Z. Expression and prognostic significance of CBX2 in colorectal cancer: database mining for CBX family members in malignancies and vitro analyses. Cancer Cell Int. 2021;21:449.

    Google Scholar 

  15. Rui S, Xucan T, Shixin C, Xu W, Yizhong J, Zhenglin W, et al. CBX2 deletion suppresses growth and metastasis of colorectal cancer by Mettl3-p38/ERK MAPK signalling pathway. J Cancer. 2024;15:2123–36.

    Google Scholar 

  16. Deli H, Andrew JF, Jonathan AG, Coralee ET, Joseph RB, Kirsten MT, et al. RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol. 2018;234:8597–609.

    Google Scholar 

  17. Guo X, Zhang H, He C, Qin K, Lai Q, Fang Y, et al. RUNX1 promotes angiogenesis in colorectal cancer by regulating the crosstalk between tumor cells and tumor associated macrophages. Biomark Res. 2024;12:29.

    PubMed  PubMed Central  Google Scholar 

  18. Planagumà J, Díaz-Fuertes M, Gil-Moreno A, Abal M, Monge M, García A, et al. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res. 2004;64:8846–53.

    PubMed  Google Scholar 

  19. Lina T, Yunling G, Yongqi S, Yang L, Yanshu L, Hongyan Z, et al. PAK4 phosphorylating RUNX1 promotes ERα-positive breast cancer-induced osteolytic bone destruction. Int J Biol Sci. 2020;16:2235–47.

    Google Scholar 

  20. Nicholas R, Susan MM, Laura M, Henry JMD, Kirsteen JC, Ann H, et al. RUNX1 is a driver of renal cell carcinoma correlating with clinical outcome. Cancer Res. 2020;80:2325–39.

    Google Scholar 

  21. Philip Chiu-Tsun T, Max Kam-Kwan C, Jeff Yat-Fai C, Alex Siu-Wing C, Dongmei Z, Chunjie L, et al. Hematopoietic transcription factor RUNX1 is essential for promoting macrophage-myofibroblast transition in non-small-cell lung carcinoma. Adv Sci. 2023;11:e2302203.

    Google Scholar 

  22. Qingyuan L, Qiuhua L, Chengcheng H, Yuxin F, Qun Y, Yue Z, et al. RUNX1 promotes tumour metastasis by activating the Wnt/β-catenin signalling pathway and EMT in colorectal cancer. J Exp Clin Cancer Res. 2019;38:334.

    Google Scholar 

  23. Qingyuan L, Qiuhua L, Chengcheng H, Haonan Z, Xingzhu P, Haolin L, et al. RUNX1 regulates the proliferation and chemoresistance of colorectal cancer through the Hedgehog signaling pathway. J Cancer. 2021;12:6363–71.

    Google Scholar 

  24. Nadin HS, Dana MZ, Nour NAJ, Salma HM, Hussein HI, Hany AO. The interplay of p38 MAPK signaling and mitochondrial metabolism, a dynamic target in cancer and pathological contexts. Biochem Pharmacol. 2024;225:116307.

    Google Scholar 

  25. Yaping Y, Tengkun D, Mengmeng G, Xu Z, Chao C, Ya Z, et al. A review of non-classical MAPK family member, MAPK4: a pivotal player in cancer development and therapeutic intervention. Int J Biol Macromol. 2024;271:132686.

    Google Scholar 

  26. Sanz-Garcia E, Argiles G, Elez E, Tabernero J. BRAF mutant colorectal cancer: prognosis, treatment, and new perspectives. Ann Oncol. 2017;28:2648–57.

    CAS  PubMed  Google Scholar 

  27. Daniel WP, Allan SH, Suzie P, Patrick SS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4:1026.

    Google Scholar 

  28. Antonella M, Stephany Yi T, Kristen Lynn K, Yuan W, Yike J, David G, et al. Polymeric nanoparticles for nonviral gene therapy extend brain tumor survival in vivo. ACS Nano. 2015;9:1236–49.

    Google Scholar 

  29. Lingmin Z, Sai D, Yanfen Z, Qingsheng P, Huan L, Ping W, et al. Homotypic targeting delivery of siRNA with artificial cancer cells. Adv Healthc Mater. 2020;9:e1900772.

    Google Scholar 

  30. Zuoming X, Yinghong W, Meng Y, Huamei W, Jian P. CBX2-mediated suppression of SIAH2 triggers WNK1 accumulations to promote glycolysis in hepatocellular carcinoma. Exp Cell Res. 2023;426:113513.

    Google Scholar 

  31. Xing Y, Ba-Tu J, Dong C, Cao X, Li B, Jia X, et al. Phosphorylation of USP27X by GSK3β maintains the stability and oncogenic functions of CBX2. Cell Death Dis. 2023;14:782.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lindsay JW, Zachary LW, Lubna Q, Tomomi MY, Miriam DP, Amber AB, et al. CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer. Oncogenesis. 2018;7:92.

    Google Scholar 

  33. Lucie JB, Chloe W, Rebecca MH, Shannon K, Ella W, Thomas F, et al. The epigenetic regulatory protein CBX2 promotes mTORC1 signalling and inhibits DREAM complex activity to drive breast cancer cell growth. Cancers. 2022;14:3491.

    Google Scholar 

  34. Zhao X, Li L, Yuan S, Zhang Q, Jiang X, Luo T. SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells. Cell Signal. 2021;88:110148.

    CAS  PubMed  Google Scholar 

  35. Wang Q, Zhang Y, Yang H. Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. Biochim Biophys Acta. 2012;1823:1807–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Pack D, Hoffman A, Pun S, Stayton P. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4:581–93.

    CAS  PubMed  Google Scholar 

  37. Liu X, Li X, Zheng P, Yang W. DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β. Cell Death Dis. 2018;9:339.

    PubMed  PubMed Central  Google Scholar 

  38. Wang B, Zhang S, Wang H, Wang M, Tao Y, Ye M, et al. Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer. Cancer Gene Ther. 2024;31:871–83.

    CAS  PubMed  Google Scholar 

  39. Zhongguang L, Bangting W, Feifei L, Yumeng G, Ning J, Jinsong W, et al. Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening. BMC Med. 2023;21:336.

Download references

Acknowledgements

We thank Xiang Wang, Min Wang, and Lianzhen Yu for their kind assistance of collecting the clinical samples. We would like to thank the Core Facility of First Affiliated Hospital of Nanjing Medical University for providing laboratory instruments.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82202828, 82104089 and 82000621), The Friendship Hospital of Ili Kazkh Autonomous Prefecture (yl2023ms05; yl2023ms and YJC2024A14) and Jiangsu Association for Science and Technology (BE2022704, BE2023779). Jiangsu Province Hospital Clinical Capacity Enhancement Project (JSPH-MB-2022-10).

Author information

Author notes

  1. These authors contributed equally: Bangting Wang, Shijie Zhang, Yumeng Guo.

Authors and Affiliations

  1. Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University and Jiangsu Province Hospital, Nanjing, Jiangsu, China

    Bangting Wang, Shijie Zhang, Hao Wu, Jiankun Wang, Yan Wang & Li Liu

  2. The Friendship Hospital of Ili Kazkh Autonomous Prefecture, Ili & Jiangsu Joint Institute of Health, Yining, China

    Bangting Wang & Yan Wang

  3. Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yumeng Guo

  4. Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia

    Wenqing Gao

  5. College of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China

    Chunming Tang

Authors
  1. Bangting Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Shijie Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yumeng Guo
    View author publications

    Search author on:PubMed Google Scholar

  4. Wenqing Gao
    View author publications

    Search author on:PubMed Google Scholar

  5. Hao Wu
    View author publications

    Search author on:PubMed Google Scholar

  6. Jiankun Wang
    View author publications

    Search author on:PubMed Google Scholar

  7. Yan Wang
    View author publications

    Search author on:PubMed Google Scholar

  8. Chunming Tang
    View author publications

    Search author on:PubMed Google Scholar

  9. Li Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

SZ, BW and CT designed the study; BW, SZ, HW, YG, CT and WG performed the experiments; BW, SZ and CT analyzed the data; LL and YW supervised the work; and BW, SZ, JW, YG, CT and WG wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yan Wang, Chunming Tang or Li Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The human study was approved by the Ethical Committee of Medical Research, The First Affiliated Hospital with Nanjing Medical University, and informed consent was obtained from all participants (2018-SR-258). All animal experimental protocols were approved by the Ethical Committee of Medical Research, Nanjing Medical University (IACUC-2207042). No blinding was done to both human and animal studies. The sample sizes for animal studies are three to six for each independent experiments as described in the relevant figure legends.

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

Wang, B., Zhang, S., Guo, Y. et al. CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis. Oncogene 44, 909–926 (2025). https://doi.org/10.1038/s41388-025-03331-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-025-03331-1

Search

Advanced search

Quick links