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IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma

Oncogene volume 40, pages 5393–5402 (2021)Cite this article

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Abstract

Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138+ cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.

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Fig. 1: IDH2 is essential for MM initiation and development.
Fig. 2: Knockdown of IDH2 expression in LP-1 cells resulted in decreased proliferation, increased apoptosis, and cell cycle arrest.
Fig. 3: The effect of IDH2 on the histone methylation and 5-mC DNA methylation in myeloma cells.
Fig. 4: The effect of IDH2 on m6A methylation in myeloma cells.
Fig. 5: The IDH2/FTO/m6A axis regulates WNT7B expression.
Fig. 6: m6A reader protein YTHDF2 is essential for WNT7B m6A modification.

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Funding

The research leading to these results has received funding from Natural Science Foundation of Jiangsu Province China (BK20201408), Clinical Key Diagnosis and Treatment Technologies in Suzhou City (LCZX201805), Jiangsu Social Development Project-New Clinical Diagnosis and Treatment Technology (BE2019664), Scientific and Technological Projects of People’s Livelihood in Suzhou City (SS201856), The Fifth Phase of “333 High-level Talents Training Project” in Jiangsu Province (BRA2018138) and National Clinical Research Center for Hematologic Diseases.

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Authors and Affiliations

  1. Department of Cell Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China

    Sha Song, Gao Fan, Qi Su, Zhiming Wang, Zhou Jin & Wenzhuo Zhuang

  2. School of Life Sciences, Westlake University, Hangzhou, China

    Sha Song

  3. Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Qi Li, Xinyun Zhang, Xiaofeng Xue & Bingzong Li

  4. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

    Chen’ao Qian

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WZ and BL designed the research, SS and GF performed research, SS and QL wrote the paper, XZ, XX, and ZW performed research and modified the paper, CQ analyzed data.

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Correspondence to Bingzong Li or Wenzhuo Zhuang.

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Song, S., Fan, G., Li, Q. et al. IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma. Oncogene 40, 5393–5402 (2021). https://doi.org/10.1038/s41388-021-01939-7

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