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:

Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma

Oncogene volume 44, pages 3333–3349 (2025) Cite this article

Subjects

A Correction to this article was published on 15 April 2026

This article has been updated

Abstract

Glioblastoma (GBM) is an incurable disease with a poor prognosis. However, the potential impact of steroid receptor coactivator-1 (SRC-1) on N6-methyladenosine (m6A) RNA modification and its role in promoting malignant progression in GBM remain unclear. The relationship between SRC-1 and the m6A “writer” protein, methyltransferase 3 (METTL3), was analyzed using data from the CGGA database. Dot blot and MeRIP‒qPCR were performed to evaluate the effects of SRC-1 knockdown or overexpression on the level of m6A modification in GBM. The biological functions of SRC-1 in regulating METTL3 in GBM were evaluated by assessing its effects on proliferation, migration, cell cycle, colony formation, and apoptosis in vitro and the tumor volume/weight of nude mice xenografted with GBM cells in vivo. Co-IP, immunofluorescence, dual-luciferase, and ChIP‒qPCR assays were subsequently conducted. By analyzing the CGGA database, we determined that SRC-1 has a close positive relationship with METTL3 in GBM. SRC-1 significantly increased the m6A RNA modification level in GBM, SRC-1 knockdown markedly inhibited c-Myc m6A methylation and mRNA stability by suppressing METTL3, and SRC-1 overexpression led to hypermethylation by increasing METTL3. SRC-1 knockdown inhibited the proliferation, migration, apoptosis resistance, and S and G2/M phases of GBM cells in vitro. Mechanically, SRC-1 interacted with the heterodimer of NF-κB p50/p65, whereby p65 activated METTL3 by directly binding to a specific region of its promoter (+18 to +27 bp), thereby increasing the m6A modification of c-Myc and ultimately promoting GBM progression. Importantly, both SRC-1 knockdown and treatment with bufalin, an SRC inhibitor, reduced GBM progression. In conclusion, this study provides the first comprehensive evidence that SRC-1 facilitates GBM progression by binding to NF-κB and regulating METTL3-mediated m6A modification of c-Myc, offering new insights into potential therapeutic strategies for GBM.

The alternative text for this image may have been generated using AI.

Schematic diagram of the mechanism revealed in this research. SRC-1 regulates METTL3-mediated m6A RNA modification of c-Myc to promote GBM progression by binding to the NF-κB transcription factor. Created in BioRender. https://BioRender.com.

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: SRC-1 affects the protein expression of c-Myc in GBM cells by regulating METTL3.
The alternative text for this image may have been generated using AI.
Fig. 2: SRC-1 affects m6A modification in GBM cells by regulating METTL3.
The alternative text for this image may have been generated using AI.
Fig. 3: SRC-1 promotes GBM cell proliferation and migration by regulating METTL3 in vitro.
The alternative text for this image may have been generated using AI.
Fig. 4: SRC-1 affects the GBM cell cycle and apoptosis by regulating METTL3 in vitro.
The alternative text for this image may have been generated using AI.
Fig. 5: SRC-1 works with NF-κB to upregulate the expression of METTL3.
The alternative text for this image may have been generated using AI.
Fig. 6: SRC-1 serves as a coactivator for NF-κB to promote METTL3 promoter activity to activate methylation.
The alternative text for this image may have been generated using AI.
Fig. 7: SRC-1 promotes GBM progression by regulating METTL3 in vivo.
The alternative text for this image may have been generated using AI.
Fig. 8: Inhibiting SRC-1 with bufalin suppresses GBM progression by regulating METTL3 in vivo.
The alternative text for this image may have been generated using AI.
Fig. 9: SRC-1 promotes orthotopic GBM growth by regulating METTL3 in vivo.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Change history

  • 13 April 2026

    The original online version of this article was revised: Following the publication of this article, the authors noted an error in the IP blots included in Figure 5F. The representative Co-IP blots for p50 in U87-MG cells and p65 in LN229 cells were inadvertently duplicated.

  • 15 April 2026

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-026-03788-8

References

  1. Berger TR, Wen PY, Lang-Orsini M, Chukwueke UN. World Health Organization 2021 classification of central nervous system tumors and implications for therapy for adult-type gliomas: a review. JAMA Oncol. 2022;8:1493–501.

    Article  PubMed  Google Scholar 

  2. Barbagallo GMV, Certo F, Di Gregorio S, Maione M, Garozzo M, Peschillo S, et al. Recurrent high-grade glioma surgery: a multimodal intraoperative protocol to safely increase extent of tumor resection and analysis of its impact on patient outcome. Neurosurg Focus. 2021;50:E20.

    Article  PubMed  Google Scholar 

  3. Verdugo E, Puerto I, Medina MA. An update on the molecular biology of glioblastoma, with clinical implications and progress in its treatment. Cancer Commun. 2022;42:1083–111.

    Article  Google Scholar 

  4. Yang Y, van der Klaauw AA, Zhu L, Cacciottolo TM, He Y, Stadler LKJ, et al. Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis. Nat Commun. 2019;10:1718.

    Article  PubMed  PubMed Central  Google Scholar 

  5. York B, O’Malley BW. Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem. 2010;285:38743–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sahar S, Reddy MA, Wong C, Meng L, Wang M, Natarajan R. Cooperation of SRC-1 and p300 with NF-kappaB and CREB in angiotensin II-induced IL-6 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2007;27:1528–34.

    Article  CAS  PubMed  Google Scholar 

  7. Charlier TD, Lakaye B, Ball GF, Balthazart J. Steroid receptor coactivator SRC-1 exhibits high expression in steroid-sensitive brain areas regulating reproductive behaviors in the quail brain. Neuroendocrinology. 2002;76:297–315.

    Article  CAS  PubMed  Google Scholar 

  8. Yuan Y, Xu J. Loss-of-function deletion of the steroid receptor coactivator-1 gene in mice reduces estrogen effect on the vascular injury response. Arterioscler Thromb Vasc Biol. 2007;27:1521–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang S, Yuan Y, Liao L, Kuang SQ, Tien JC, O’Malley BW, et al. Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation. Proc Natl Acad Sci USA. 2009;106:151–6.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Y, Duan C, Bian C, Xiong Y, Zhang J. Steroid receptor coactivator-1: a versatile regulator and promising therapeutic target for breast cancer. J Steroid Biochem Mol Biol. 2013;138:17–23.

    Article  CAS  PubMed  Google Scholar 

  11. Guo P, Chen Q, Peng K, Xie J, Liu J, Ren W, et al. Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling. Oncogene. 2022;41:2846–59.

    Article  CAS  PubMed  Google Scholar 

  12. Choi SR, Wang HM, Shin MH, Lim HS. Hydrophobic tagging-mediated degradation of transcription coactivator SRC-1. Int J Mol Sci. 2021;22:6407.

  13. Ward E, Vareslija D, Charmsaz S, Fagan A, Browne AL, Cosgrove N, et al. Epigenome-wide SRC-1-mediated gene silencing represses cellular differentiation in advanced breast cancer. Clin Cancer Res. 2018;24:3692–703.

    Article  CAS  PubMed  Google Scholar 

  14. Gong M, Wang X, Mu L, Wang Y, Pan J, Yuan X, et al. Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway. Cancer Sci. 2021;112:604–18.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Shi W. Steroid receptor coactivator-1 regulates glioma angiogenesis through polyomavirus enhancer activator 3 signaling. Biochem Cell Biol. 2019;97:488–96.

    Article  CAS  PubMed  Google Scholar 

  16. Hernandez-Hernandez OT, Gonzalez-Garcia TK, Camacho-Arroyo I. Progesterone receptor and SRC-1 participate in the regulation of VEGF, EGFR and Cyclin D1 expression in human astrocytoma cell lines. J Steroid Biochem Mol Biol. 2012;132:127–34.

    Article  CAS  PubMed  Google Scholar 

  17. Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29:1343–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deng X, Su R, Weng H, Huang H, Li Z, Chen J. RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28:507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen XY, Zhang J, Zhu JS. The role of m(6)A RNA methylation in human cancer. Mol Cancer. 2019;18:103.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer. 2020;19:88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zheng ZH, Zhang GL, Jiang RF, Hong YQ, Zhang QY, He JP, et al. METTL3 is essential for normal progesterone signaling during embryo implantation via m6A-mediated translation control of progesterone receptor. Proc Natl Acad Sci USA. 2023;120:e2214684120.

  22. Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019;18:112.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ying X, Jiang X, Zhang H, Liu B, Huang Y, Zhu X, et al. Programmable N6-methyladenosine modification of CDCP1 mRNA by RCas9-methyltransferase like 3 conjugates promotes bladder cancer development. Mol Cancer. 2020;19:169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zheng R, Zhang K, Tan S, Gao F, Zhang Y, Xu W, et al. Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD4 via METTL3-eIF3h interaction. Mol Cancer. 2022;21:49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yue B, Song C, Yang L, Cui R, Cheng X, Zhang Z, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Mol Cancer. 2019;18:142.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Du QY, Huo FC, Du WQ, Sun XL, Jiang X, Zhang LS, et al. METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA. Oncogene. 2022;41:4420–32.

    Article  CAS  PubMed  Google Scholar 

  27. Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, et al. The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells. Cancer Discov. 2021;11:480–99.

    Article  CAS  PubMed  Google Scholar 

  28. Yin J, Ding F, Cheng Z, Ge X, Li Y, Zeng A, et al. METTL3-mediated m6A modification of LINC00839 maintains glioma stem cells and radiation resistance by activating Wnt/beta-catenin signaling. Cell Death Dis. 2023;14:417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang ZW, Teng X, Zhao F, Ma C, Zhang J, Xiao LF, et al. METTL3 regulates m(6)A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma. Cell Rep. 2022;41:111530.

    Article  CAS  PubMed  Google Scholar 

  30. Han J, Du S, Wu C, Qiu M, Su L, Zhao Z, et al. METTL3 participates in glioma development by regulating the methylation level of COL4A1. J BUON. 2021;26:1556–62.

    PubMed  Google Scholar 

  31. Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018;37:522–33.

    Article  CAS  PubMed  Google Scholar 

  32. Li F, Chen S, Yu J, Gao Z, Sun Z, Yi Y, et al. Interplay of m(6) A and histone modifications contributes to temozolomide resistance in glioblastoma. Clin Transl Med. 2021;11:e553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wasylishen AR, Penn LZ. Myc: the beauty and the beast. Genes Cancer. 2010;1:532–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fukasawa K, Kadota T, Horie T, Tokumura K, Terada R, Kitaguchi Y, et al. CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway. Oncogene. 2021;40:2803–15.

    Article  CAS  PubMed  Google Scholar 

  35. Mu Q, Chai R, Pang B, Yang Y, Liu H, Zhao Z, et al. Identifying predictors of glioma evolution from longitudinal sequencing. Sci Transl Med. 2023;15:eadh4181.

    Article  CAS  PubMed  Google Scholar 

  36. Yuan XN, Shao YC, Guan XQ, Liu Q, Chu MF, Yang ZL, et al. METTL3 orchestrates glycolysis by stabilizing the c-Myc/WDR5 complex in triple-negative breast cancer. Biochim Biophys Acta Mol Cell Res. 2024;1871:119716.

    Article  CAS  PubMed  Google Scholar 

  37. Guo S, Chen F, Li L, Dou S, Li Q, Huang Y, et al. Intracellular Fusobacterium nucleatum infection increases METTL3-mediated m6A methylation to promote the metastasis of esophageal squamous cell carcinoma. J Adv Res. 2024;61:165–78.

    Article  CAS  PubMed  Google Scholar 

  38. Shi Y, Dou Y, Zhang J, Qi J, Xin Z, Zhang M, et al. The RNA N6-methyladenosine methyltransferase METTL3 promotes the progression of kidney cancer via N6-methyladenosine-dependent translational enhancement of ABCD1. Front Cell Dev Biol. 2021;9:737498.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Na SY, Lee SK, Han SJ, Choi HS, Im SY, Lee JW. Steroid receptor coactivator-1 interacts with the p50 subunit and coactivates nuclear factor kappaB-mediated transactivations. J Biol Chem. 1998;273:10831–4.

    Article  CAS  PubMed  Google Scholar 

  40. Wang Y, Lonard DM, Yu Y, Chow DC, Palzkill TG, Wang J, et al. Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res. 2014;74:1506–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tong Z, Zhang Y, Guo P, Wang W, Chen Q, Jin J, et al. Steroid receptor coactivator 1 promotes human hepatocellular carcinoma invasiveness through enhancing MMP-9. J Cell Mol Med. 2024;28:e18171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee Y, Heo J, Jeong H, Hong KT, Kwon DH, Shin MH, et al. Targeted degradation of transcription coactivator SRC-1 through the N-degron pathway. Angew Chem Int Ed Engl. 2020;59:17548–55.

    Article  CAS  PubMed  Google Scholar 

  43. Qiao Z, Li Y, Cheng Y, Li S, Liu S. SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc. Cell Biosci. 2023;13:203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Iaiza A, Tito C, Ianniello Z, Ganci F, Laquintana V, Gallo E, et al. METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors. Clin Epigenet. 2021;13:173.

    Article  CAS  Google Scholar 

  45. Visvanathan A, Patil V, Abdulla S, Hoheisel JD, Somasundaram K. N(6)-methyladenosine landscape of glioma stem-like cells: METTL3 is essential for the expression of actively transcribed genes and sustenance of the oncogenic signaling. Genes 2019;10:141.

  46. Cahill KE, Morshed RA, Yamini B. Nuclear factor-kappaB in glioblastoma: insights into regulators and targeted therapy. Neuro Oncol. 2016;18:329–39.

    Article  CAS  PubMed  Google Scholar 

  47. Eluard B, Thieblemont C, Baud V. NF-kappaB in the New Era of Cancer Therapy. Trends Cancer. 2020;6:677–87.

    Article  CAS  PubMed  Google Scholar 

  48. Gao B, Guo L, Luo D, Jiang Y, Zhao J, Mao C, et al. Steroid receptor coactivator-1 interacts with NF-kappaB to increase VEGFC levels in human thyroid cancer. Biosci Rep. 2018;38:BSR20180394.

  49. Gao L, Rabbitt EH, Condon JC, Renthal NE, Johnston JM, Mitsche MA, et al. Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J Clin Investig. 2015;125:2808–24.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Feng Y, Dong H, Sun B, Hu Y, Yang Y, Jia Y, et al. METTL3/METTL14 transactivation and m(6)A-dependent TGF-beta1 translation in activated Kupffer cells. Cell Mol Gastroenterol Hepatol. 2021;12:839–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Soumoy L, Ghanem GE, Saussez S, Journe F. Bufalin for an innovative therapeutic approach against cancer. Pharmacol Res. 2022;184:106442.

    Article  CAS  PubMed  Google Scholar 

  52. Liu T, Jia T, Yuan X, Liu C, Sun J, Ni Z, et al. Development of octreotide-conjugated polymeric prodrug of bufalin for targeted delivery to somatostatin receptor 2 overexpressing breast cancer in vitro and in vivo. Int J Nanomed. 2016;11:2235–50.

    CAS  Google Scholar 

  53. Shen S, Zhang Y, Wang Z, Gong LiuR. X. Bufalin induces the interplay between apoptosis and autophagy in glioma cells through endoplasmic reticulum stress. Int J Biol Sci. 2014;10:212–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang Y, Dong Y, Melkus MW, Yin S, Tang SN, Jiang P, et al. Role of P53-senescence induction in suppression of LNCaP prostate cancer growth by cardiotonic compound Bufalin. Mol Cancer Ther. 2018;17:2341–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yang L, Zhou F, Zhuang Y, Liu Y, Xu L, Zhao H, et al. Acetyl-bufalin shows potent efficacy against non-small-cell lung cancer by targeting the CDK9/STAT3 signalling pathway. Br J Cancer. 2021;124:645–57.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Postgraduate Training Fund of Dalian Medical University and the Educational Commission of Liaoning Province of China (No. LZ2019026).

Author information

Author notes

  1. These authors contributed equally: Liang Liu, Rui Wang, Ke Cheng.

Authors and Affiliations

  1. The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

    Liang Liu, Rui Wang, Ke Cheng, Chunmei Bai, Yuke Ji, Yifei Zhang, Haoran Yang, Miaomiao Gong, Fang Xie, Jinjin Pan & Yuhui Yuan

  2. College of Pharmacy, Dalian Medical University, Dalian, China

    Rui Wang

  3. The First Affiliated Hospital, Dalian Medical University, Dalian, China

    Yongshun Zhao

Authors
  1. Liang Liu
    View author publications

    Search author on:PubMed Google Scholar

  2. Rui Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Ke Cheng
    View author publications

    Search author on:PubMed Google Scholar

  4. Chunmei Bai
    View author publications

    Search author on:PubMed Google Scholar

  5. Yuke Ji
    View author publications

    Search author on:PubMed Google Scholar

  6. Yifei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  7. Haoran Yang
    View author publications

    Search author on:PubMed Google Scholar

  8. Miaomiao Gong
    View author publications

    Search author on:PubMed Google Scholar

  9. Fang Xie
    View author publications

    Search author on:PubMed Google Scholar

  10. Yongshun Zhao
    View author publications

    Search author on:PubMed Google Scholar

  11. Jinjin Pan
    View author publications

    Search author on:PubMed Google Scholar

  12. Yuhui Yuan
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Liang Liu, Jinjin Pan, and Yuhui Yuan conceived and designed the experiments. Liang Liu, Rui Wang, Ke Cheng, Chunmei Bai, Yuke Ji, Yifei Zhang, Haoran Yang, Miaomiao Gong, Fang Xie, and Yongshun Zhao collected, analyzed, and interpreted the experimental data. Liang Liu and Rui Wang drafted the manuscript. Yongshun Zhao, Jinjin Pan, and Yuhui Yuan reviewed the manuscript. All the authors revised the manuscript critically and approved the final version.

Corresponding authors

Correspondence to Yongshun Zhao, Jinjin Pan or Yuhui Yuan.

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

Liu, L., Wang, R., Cheng, K. et al. Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma. Oncogene 44, 3333–3349 (2025). https://doi.org/10.1038/s41388-025-03494-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-025-03494-x

Search

Advanced search

Quick links