Zhang Lin, Zhao Xian, Hu Jingyan, Li Tingting, Chen Hong-Zhuan, Zhang Ao, Wang Hao, Yu Jianxiu, Zhang Liang
Department of Pharmacology and Chemical Biology, State Key Laboratory of Systems Medicine for Cancer, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Nat Commun. 2025 Apr 28;16(1):3966. doi: 10.1038/s41467-025-59119-0.
Cancer cells exploit altered metabolic pathways to dynamically regulate epigenetic methylation and thus promote tumorigenesis and metastasis. In various human cancers, such as lung adenocarcinoma, the level of a key cellular metabolite, S-adenosylmethionine (SAM), is prominently upregulated for RNA hypermethylation as the methyl donor. However, the specific mechanisms by which cancer cells produce SAM to sustain RNA methylation remain elusive. Here, we demonstrate that PRPS2, a phosphoribosyl pyrophosphate synthetase isoform involved in the first and rate-limiting step of the purine biosynthesis pathway, exhibits distinct oncogenic functionality in regulating RNA methylation, unlike its homolog PRPS1. PRPS2 utilizes four non-conserved key residues to bypass the typical ADP/GDP allosteric feedback inhibition, enabling sustained excess production of newly synthesized ATP. Moreover, PRPS2 stabilizes methionine adenosyltransferase 2 A (MAT2A) through direct interactions to positively stimulate ATP utilization and SAM synthesis for RNA mA specific methylation via the WTAP/METTL3/METTL14 methyltransferase complex, thereby promoting lung tumorigenesis. Our study links nucleotide biosynthesis with RNA epigenetics in cancer progression through the PRPS2-MAT2A-WTAP/METTL3/METTL14 axis, and elucidates both enzyme-dependent and independent functions of PRPS2. These findings have significant implications for developing targeted therapies for cancers associated with PRPS2 abnormalities.
癌细胞利用改变的代谢途径来动态调节表观遗传甲基化，从而促进肿瘤发生和转移。在各种人类癌症中，如肺腺癌，关键细胞代谢物S-腺苷甲硫氨酸（SAM）的水平显著上调，作为甲基供体用于RNA超甲基化。然而，癌细胞产生SAM以维持RNA甲基化的具体机制仍不清楚。在这里，我们证明，PRPS2，一种参与嘌呤生物合成途径第一步和限速步骤的磷酸核糖焦磷酸合成酶同工型，与其同源物PRPS1不同，在调节RNA甲基化方面表现出独特的致癌功能。PRPS2利用四个非保守关键残基绕过典型的ADP/GDP变构反馈抑制，从而持续过量产生新合成的ATP。此外，PRPS2通过直接相互作用稳定甲硫氨酸腺苷转移酶2A（MAT2A），以正向刺激ATP利用和通过WTAP/METTL3/METTL14甲基转移酶复合物进行RNA mA特异性甲基化的SAM合成，从而促进肺肿瘤发生。我们的研究通过PRPS2-MAT2A-WTAP/METTL3/METTL14轴将核苷酸生物合成与癌症进展中的RNA表观遗传学联系起来，并阐明了PRPS2的酶依赖性和非依赖性功能。这些发现对开发针对与PRPS2异常相关癌症的靶向治疗具有重要意义。
