Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Cheng, Ying; Gao, Zhuying; Zhang, Tiantian; Wang, Yuhua; Xie, Xueqin; Han, Guoqiang; Li, Yashu; Yin, Rong; Chen, Yilin; Wang, Peipei; Hu, Jin; Zhang, Tong; Guo, Chi; Chai, Jihua; Wang, Jing; Cui, Manman; Gao, Kun; Liu, Weidong; Yao, Shuxin; Lu, Pengbo; Cao, Zhe; Zheng, Yanbing; Chang, Jiangfang; Liu, Zheming; Song, Qibin; Li, Weiming; Zhou, Fuling; Zhang, Haojian

doi:10.1016/j.stem.2022.12.003

Cited by 30 publications

(13 citation statements)

References 50 publications

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“…METTL3/IGF2BP2 regulates m 6 A modification of PLK1 and increases its stability and expression, leading to radio-resistance in pancreatic adenocarcinoma [ 52 ]. IGF2BP2 improves PRMT6 expression for leukemia stem cell (LSC) maintenance and acute myeloid leukemia development via stabilizing its transcript in an m 6 A-dependent form [ 53 ]. NFE2L2, upregulated by ALKBH5/IGF2BP2-mediated m 6 A methylation after transcription, inhibits ferroptosis of hypopharyngeal squamous cell carcinoma [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Zhu

Ling

2023

Biomark Res

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N6-methyladenosine (m6A) is the most prevalent and well-characterized internal chemical modification in eukaryotic RNA, influencing gene expression and phenotypic changes by controlling RNA fate. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) preferentially function as m6A effector proteins, promoting stability and translation of m6A-modified RNAs. IGF2BPs, particularly IGF2BP1 and IGF2BP3, are widely recognized as oncofetal proteins predominantly expressed in cancer rather than normal tissues, playing a critical role in tumor initiation and progression. Consequently, IGF2BPs hold potential for clinical applications and serve as a good choice for targeted treatment strategies. In this review, we discuss the functions and mechanisms of IGF2BPs as m6A readers and explore the therapeutic potential of targeting IGF2BPs in human cancer.

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Section: Introductionmentioning

confidence: 99%

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Zhu

Ling

2023

Biomark Res

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“…This could indicate posttranscriptional regulation of Prmt6, potentially by an adipocyte associated microRNA. Alternatively, Prmt6 transcript stability could be regulated by RNA-methylation as was recently described for Prmt6 28 . There is also evidence for regulation of Prmt6 by proteasomal degradation 29 , 30 .…”

Section: Discussionmentioning

confidence: 92%

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

Gerstner,

Heller,

Fechner

et al. 2024

Sci Rep

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The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma–C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.

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“… 330 In AML, IGF2BP2 stabilizes PRMT6 mRNA through m6A-dependemt manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression, thus decreasing docosahexaenoic acid levels and promoting LSC maintenance. 331 HNRNPA2B1 participates in enhancing fatty acid metabolism of GC via stabilizing RPRD1B mRNA, which facilitated uptake and synthesis of FA by transcriptionally activating c-Jun/c-Fos, further upregulated SREBP1. 332 Abrogation of HNRNPA2B1 inhibits de novo fatty acid synthesis in ESCA cells though downregulating expression of ACLY and ACC1.…”

Section: Rna Modifications and Cellular Metabolismmentioning

confidence: 99%

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

Liu,

Zheng,

et al. 2024

Sig Transduct Target Ther

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Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells. Relevant studies have been constantly making inroads in our understanding of pathophysiology, and inspiring development of therapeutics. As a crucial component of epigenetics at post-transcription level, RNA modification significantly determines RNA fates, further affecting various biological processes and cellular phenotypes. To be noted, immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts. In this review, we characterize the distribution features, modifying mechanisms and biological functions of 8 RNA modifications, including N6-methyladenosine (m6A), N6,2′-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N4-acetylcytosine (ac4C), N7-methylguanosine (m7G), Pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing, which are relatively the most studied types. Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described, categorized as glucose, lipid, amino acid, and mitochondrial metabolism. And we highlight the regulation of RNA modifications on immunometabolism, further influencing immune responses. Above all, we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy, progression of RNA modification-targeted agents, and its potential in RNA-targeted therapeutics. Eventually, we give legitimate perspectives for future researches in this field from methodological requirements, mechanistic insights, to therapeutic applications.

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Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Cited by 30 publications

References 50 publications

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

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