The m^⁵C methyltransferase NSUN2 promotes progression of acute myeloid leukemia by regulating serine metabolism.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-05-07 DOI:10.1016/j.celrep.2025.115661

Songyu Li, Ya Liu, Xiang Wu, Minjia Pan, Hongxia Zhao, Yunguang Hong, Qinghua Zhang, Shushu Hu, Aorong Ouyang, Guangru Li, Minhui Wu, Shanshan Fan, Zhirong Jia, Shanchao Zhao, Guocai Wu, Xiangwei Gao, Zhigang Yang, Zhanghui Chen

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引用次数: 0

Abstract

Acute myeloid leukemia (AML) is one of the most prevalent heterogeneous hematologic malignancies with a complicated etiology. RNA post-transcriptional modifications have been linked to the incidence and progression of AML, while the detailed mechanism remains to be elucidated. In this study, we find that NOP2/Sun domain family member 2 (NSUN2), a methyltransferase of 5-methylcytosine (m^⁵C) RNA methylation, is upregulated in AML and predicts a poor prognosis for patients with AML. Knockdown of NSUN2 in AML cells inhibits proliferation and colony formation and promotes apoptosis. Depletion of NSUN2 in AML mice reduces the tumor burden and prolongs survival. Mechanistically, NSUN2 promotes the expression of phosphoglycerate dehydrogenase (PHGDH) and serine hydroxymethyltransferase 2 (SHMT2), two key enzymes in the serine/glycine biosynthesis pathway, by stabilizing the corresponding mRNAs through regulation of m⁵C modifications. Overall, our findings demonstrate a critical role of NSUN2 in AML development and highlight the therapeutic potential of targeting the NSUN2/m^⁵C axis for the treatment of this cancer.

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m5C甲基转移酶NSUN2通过调节丝氨酸代谢促进急性髓系白血病的进展。

急性髓系白血病（AML）是最常见的异质性血液系统恶性肿瘤之一，病因复杂。RNA转录后修饰与AML的发生和进展有关，但其具体机制仍有待阐明。在这项研究中，我们发现NOP2/Sun结构域家族成员2 (NSUN2)，一种5-甲基胞嘧啶（m5C） RNA甲基化的甲基转移酶，在AML中上调，并预测AML患者的不良预后。AML细胞中NSUN2的敲低抑制增殖和集落形成，促进细胞凋亡。AML小鼠中NSUN2的缺失减少了肿瘤负荷并延长了生存期。在机制上，NSUN2通过调节m5C修饰稳定相应mrna，从而促进丝氨酸/甘氨酸生物合成途径中的两个关键酶磷酸甘油酸脱氢酶（PHGDH）和丝氨酸羟甲基转移酶2 （SHMT2）的表达。总的来说，我们的研究结果证明了NSUN2在AML发展中的关键作用，并强调了靶向NSUN2/m5C轴治疗这种癌症的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.