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

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

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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.

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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.

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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).

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

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  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

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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.

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Correspondence to Chunyan Gu or Ye Yang.

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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

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