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:

YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis

Oncogene volume 41, pages 1482–1491 (2022)Cite this article

Subjects

Abstract

Multiple myeloma (MM) is still incurable partially due to lacking effective therapeutic targets. Aberrant N6-methyladenosine (m6A) RNA modification plays a vital role in many cancers, however few researches are executed in MM. We first screened the m6A-related genes in MM patient cohorts and correlated these genes with patient outcomes. We found that YTHDF2, a well-recognized m6A reader, was increased in MM patients and associated with poor outcomes. Decreased YTHDF2 expression hampered MM cell proliferation in vitro and in vivo, while enforced YTHDF2 expression reversed those effects. The analyses of m6A-RIP-seq and RIP-PCR indicated that STAT5A was the downstream target of YTHDF2, which was binding to the m6A modification site of STAT5A to promote its mRNA degradation. ChIP-seq and PCR assays revealed that STAT5A suppressed MM cell proliferation by occupying the transcription site of MAP2K2 to decrease ERK phosphorylation. In addition, we confirmed that YTHDF2 mediated the unphosphorylated form of STAT5A to inhibit the expression of MAP2K2/p-ERK. In conclusion, our study highlights that YTHDF2/STAT5A/MAP2K2/p-ERK axis plays a key role in MM proliferation and targeting YTHDF2 may be a promising therapeutic strategy.

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

Access options

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: Elevated YTHDF2 expression is associated with poor survival of MM patients.
Fig. 2: YTHDF2 promotes m6A methylation and cellular proliferation in MM.
Fig. 3: Decreased YTHDF2 retards tumor growth in MM xenograft model.
Fig. 4: STAT5A is identified as a potential target of YTHDF2 based on MeRIP-seq and GEP database.
Fig. 5: Upregulation of STAT5A upon YTHDF2 knockdown abrogates the proliferation ability of MM cells in vitro.
Fig. 6: The potential mechanism of YTHDF2/STAT5A in MM progression is associated with MAPK signaling pathway via targeting MA2PK2.
Fig. 7: YTHDF2/STAT5A/MAP2K2/p-ERK axis is participated in facilitating MM cell proliferation.
Fig. 8: YTHDF2-mediated u-STAT5A suppresses MAP2K2/p-ERK expression.

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  PubMed  Google Scholar 

  2. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66:443–59.

    Article  PubMed  Google Scholar 

  3. Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV, et al. Multiple myeloma. Nat Rev Dis Prim. 2017;3:17046.

    Article  PubMed  Google Scholar 

  4. Manasanch EE, Orlowski RZ. Proteasome inhibitors in cancer therapy. Nat Rev Clin Oncol. 2017;14:417–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Röllig C, Knop S, Bornhäuser M. Multiple myeloma. Lancet. 2015;385:2197–208.

    Article  PubMed  Google Scholar 

  6. Bianchi G, Anderson KC. Understanding biology to tackle the disease: multiple myeloma from bench to bedside, and back. CA Cancer J Clin. 2014;64:422–44.

    Article  PubMed  Google Scholar 

  7. Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao Z, Chen Y, Francisco NM, Zhang Y, Wu M. The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm Sin B. 2018;8:539–51.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rajkumar SV. Multiple myeloma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91:719–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cardona-Benavides IJ, de Ramón C, Gutiérrez NC. Genetic abnormalities in multiple myeloma: prognostic and therapeutic implications. Cells. 2021;10:336.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dimopoulos K, Gimsing P, Grønbæk K. The role of epigenetics in the biology of multiple myeloma. Blood Cancer J. 2014;4:e207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brioli A, Melchor L, Cavo M, Morgan GJ. The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol. 2014;165:441–54.

    Article  PubMed  Google Scholar 

  13. van Nieuwenhuijzen N, Spaan I, Raymakers R, Peperzak V. From MGUS to multiple myeloma, a paradigm for clonal evolution of premalignant cells. Cancer Res. 2018;78:2449–56.

    Article  PubMed  Google Scholar 

  14. He L, Li H, Wu A, Peng Y, Shu G, Yin G. Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019;18:176.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Hu BB, Wang XY, Gu XY, Zou C, Gao ZJ, Zhang H, et al. N(6)-methyladenosine (m(6)A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications. Mol Cancer. 2019;18:178.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    Article  CAS  PubMed  Google Scholar 

  18. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′UTRs and near stop codons. Cell. 2012;149:1635–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen Y, Lin Y, Shu Y, He J, Gao W. Interaction between N(6)-methyladenosine (m(6)A) modification and noncoding RNAs in cancer. Mol Cancer. 2020;19:94.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bach C, Leffler M, Kroenke J, Saul D, Mougiakakos D, Mackensen A, et al. Role of N6-methyladenosine (m6A) RNA modification in multiple myeloma. Oncol Res Treat. 2019;42:123.

    Google Scholar 

  21. Bai H, Xu P, Chen B. Gene signatures and prognostic values of m6A-related genes in multiple myeloma. Curr Res Transl Med. 2021;69:103288.

    Article  PubMed  Google Scholar 

  22. Jiang F, Tang X, Tang C, Hua Z, Ke M, Wang C, et al. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA. J Hematol Oncol. 2021;14:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.

    Article  PubMed  Google Scholar 

  24. Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shen X, Zhao K, Xu L, Cheng G, Zhu J, Gan L, et al. YTHDF2 inhibits gastric cancer cell growth by regulating FOXC2 signaling pathway. Front Genet. 2020;11:592042.

    Article  CAS  PubMed  Google Scholar 

  26. Sheng H, Li Z, Su S, Sun W, Zhang X, Li L, et al. YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. Carcinogenesis. 2020;41:541–50.

    Article  CAS  PubMed  Google Scholar 

  27. Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252–61.

    Article  CAS  PubMed  Google Scholar 

  28. Huang T, Liu Z, Zheng Y, Feng T, Gao Q, Zeng W. YTHDF2 promotes spermagonial adhesion through modulating MMPs decay via m(6)A/mRNA pathway. Cell Death Dis. 2020;11:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Neuzillet C, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E. MEK in cancer and cancer therapy. Pharmacol Ther. 2014;141:160–71.

    Article  CAS  PubMed  Google Scholar 

  30. Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, et al. Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth. Proc Natl Acad Sci USA. 2013;110:10213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol. 2008;18:545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38:13–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bakhoum SF, Landau DA. Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb Perspect Med. 2017;7:a029611.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Neuse CJ, Lomas OC, Schliemann C, Shen YJ, Manier S, Bustoros M, et al. Genome instability in multiple myeloma. Leukemia. 2020;34:2887–97.

    Article  PubMed  Google Scholar 

  35. Bolli N, Avet-Loiseau H, Wedge DC, Van Loo P, Alexandrov LB, Martincorena I, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997.

    Article  PubMed  Google Scholar 

  36. Lohr JG, Stojanov P, Carter SL, Cruz-Gordillo P, Lawrence MS, Auclair D, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Robiou du Pont S, Cleynen A, Fontan C, Attal M, Munshi N, Corre J, et al. Genomics of multiple myeloma. J Clin Oncol. 2017;35:963–7.

    Article  PubMed  Google Scholar 

  38. Gu C, Wang W, Tang X, Xu T, Zhang Y, Guo M, et al. CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma. Mol Cancer. 2021;20:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang X, Guo M, Ding P, Deng Z, Ke M, Yuan Y, et al. BUB1B and circBUB1B_544aa aggravate multiple myeloma malignancy through evoking chromosomal instability. Signal Transduct Target Ther. 2021;6:361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhu H, Jia X, Wang Y, Song Z, Wang N, Yang Y, et al. M6A classification combined with tumor microenvironment immune characteristics analysis of bladder cancer. Front Oncol. 2021;11:714267.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Shen X, Hu B, Xu J, Qin W, Fu Y, Wang S, et al. The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics. Cancer Biol Med. 2020;17:937–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McClure JJ, Li X, Chou CJ. Advances and challenges of HDAC inhibitors in cancer therapeutics. Adv Cancer Res. 2018;138:183–211.

    Article  CAS  PubMed  Google Scholar 

  43. Brown S, Pawlyn C, Tillotson AL, Sherratt D, Flanagan L, Low E, et al. Bortezomib, vorinostat, and dexamethasone combination therapy in relapsed myeloma: results of the phase 2 MUK four trial. Clin Lymphoma Myeloma Leuk. 2021;21:154–61.e3.

    Article  PubMed  Google Scholar 

  44. Chen B, Li Y, Song R, Xue C, Xu F. Functions of RNA N6-methyladenosine modification in cancer progression. Mol Biol Rep. 2019;46:2567–75.

    Article  CAS  PubMed  Google Scholar 

  45. Chang YZ, Chai RC, Pang B, Chang X, An SY, Zhang KN, et al. METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF-κB to promote the malignant progression of IDH-wildtype glioma. Cancer Lett. 2021;511:36–46.

    Article  CAS  PubMed  Google Scholar 

  46. Liu Y, Liang G, Xu H, Dong W, Dong Z, Qiu Z, et al. Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance. Cell Metab. 2021;33:1221–33.

    Article  CAS  PubMed  Google Scholar 

  47. Xu Y, Liu J, Chen WJ, Ye QQ, Chen WT, Li CL, et al. Regulation of N6-methyladenosine in the differentiation of cancer stem cells and their fate. Front Cell Dev Biol. 2020;8:561703.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613.

    Article  CAS  PubMed  Google Scholar 

  49. Song P, Feng L, Li J, Dai D, Zhu L, Wang C, et al. β-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer. Mol Cancer. 2020;19:129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang L, Wan Y, Zhang Z, Jiang Y, Lang J, Cheng W, et al. FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway. RNA Biol. 2021;18:1265–78.

    Article  PubMed  Google Scholar 

  51. Cui X, Wang Z, Li J, Zhu J, Ren Z, Zhang D, et al. Cross talk between RNA N6-methyladenosine methyltransferase-like 3 and miR-186 regulates hepatoblastoma progression through Wnt/β-catenin signalling pathway. Cell Prolif. 2020;53:e12768.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Song S, Fan G, Li Q, Su Q, Zhang X, Xue X, et al. IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma. Oncogene. 2021;40:5393–402.

    Article  CAS  PubMed  Google Scholar 

  53. Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma. Int J Hematol. 2016;104:273–80.

    Article  CAS  PubMed  Google Scholar 

  54. Zhuang J, Shirazi F, Singh RK, Kuiatse I, Wang H, Lee HC, et al. Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma. Blood. 2019;133:1572–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li Z, Qian P, Shao W, Shi H, He XC, Gogol M, et al. Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 2018;28:904–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xu J, Pfarr N, Endris V, Mai EK, Md Hanafiah NH, Lehners N, et al. Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation. Oncogenesis. 2017;6:e337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heuck CJ, Jethava Y, Khan R, van Rhee F, Zangari M, Chavan S, et al. Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia. 2016;30:976–80.

    Article  CAS  PubMed  Google Scholar 

  58. Wu CJ, Sundararajan V, Sheu BC, Huang RY, Wei LH. Activation of STAT3 and STAT5 signaling in epithelial ovarian cancer progression: mechanism and therapeutic opportunity. Cancers. 2019;12:24.

    Article  PubMed Central  Google Scholar 

  59. Lauta VM. A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer. 2003;97:2440–52.

    Article  CAS  PubMed  Google Scholar 

  60. Peng Y, Li F, Zhang P, Wang X, Shen Y, Feng Y, et al. IGF-1 promotes multiple myeloma progression through PI3K/Akt-mediated epithelial-mesenchymal transition. Life Sci. 2020;249:117503.

    Article  CAS  PubMed  Google Scholar 

  61. Furigo IC, Melo HM. Lyra ESNM, Ramos-Lobo AM, Teixeira PDS, Buonfiglio DC, et al. Brain STAT5 signaling modulates learning and memory formation. Brain Struct Funct. 2018;223:2229–41.

    Article  CAS  PubMed  Google Scholar 

  62. Kimura A, Martin C, Robinson GW, Simone JM, Chen W, Wickre MC, et al. The gene encoding the hematopoietic stem cell regulator CCN3/NOV is under direct cytokine control through the transcription factors STAT5A/B. J Biol Chem. 2010;285:32704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rani A, Murphy JJ. STAT5 in cancer and immunity. J Interferon Cytokine Res. 2016;36:226–37.

    Article  CAS  PubMed  Google Scholar 

  64. Cimino G, Avvisati G, Amadori S, Cava MC, Giannarelli D, Di Nucci GD, et al. High serum IL-2 levels are predictive of prolonged survival in multiple myeloma. Br J Haematol. 1990;75:373–7.

    Article  CAS  PubMed  Google Scholar 

  65. Surbek M, Tse W, Moriggl R, Han X. A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation. Cytokine. 2021;139:155392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S, et al. The molecular classification of multiple myeloma. Blood. 2006;108:2020–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Broyl A, Hose D, Lokhorst H, de Knegt Y, Peeters J, Jauch A, et al. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients. Blood. 2010;116:2543–53.

    Article  CAS  PubMed  Google Scholar 

  68. Wei R, Zhong S, Qiao L, Guo M, Shao M, Wang S, et al. Steroid 5α-reductase type I induces cell viability and migration via nuclear factor-κB/vascular endothelial growth factor signaling pathway in colorectal cancer. Front Oncol. 2020;10:1501.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China 81970196 (to CG), 82073885 (to YY), 82003832 (to MG); Natural Science Foundation of Jiangsu Province BK20200097 (to CG); Jiangsu Postgraduate Research and Practice Innovation Program KYCX21_1769 (to RW); A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine).

Author information

Author notes

  1. These authors contributed equally: Zhen Hua, Rongfang Wei.

Authors and Affiliations

  1. Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China

    Zhen Hua, Mengjie Guo & Chunyan Gu

  2. School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China

    Zhen Hua, Rongfang Wei, Mengjie Guo, Zigen Lin, Xichao Yu, Xinying Li, Chunyan Gu & Ye Yang

Authors
  1. Zhen Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rongfang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengjie Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zigen Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xichao Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunyan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ye Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YY and CG designed and conceived the experiments. ZH and RW developed methodology and conducted most of the experiments. MG analyzed and processed the sequencing data. ZL performed the animal experiments. XY and XL acquired the data. ZH and CG drafted the manuscript. YY and CG conducted supervision and edited the manuscript.

Corresponding authors

Correspondence to Chunyan Gu or Ye Yang.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hua, Z., Wei, R., Guo, M. et al. YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis. Oncogene 41, 1482–1491 (2022). https://doi.org/10.1038/s41388-022-02191-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02191-3

This article is cited by

Search

Advanced search

Quick links

pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy