Emerging roles of m6A RNA modification in cancer therapeutic resistance

Liu, Weiwei; Zhang, Zhongyuan; Wang, Fei; Wang, Hao

doi:10.1186/s40164-023-00386-2

Cited by 10 publications

(10 citation statements)

References 186 publications

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“…The involvement of m6A modification in underlying mechanisms of resistance has been systematically summarized. 429 Herein, we put emphasis on the combined utility of targeting RNA modification to circumvent resistance and improve individualized cancer treatment.…”

Section: Clinical Implications Of Rna Modificationsmentioning

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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Section: Clinical Implications Of Rna Modificationsmentioning

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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“…Whether m6A methyltransferases can function as methylation recognition enzymes or other epigenetic factors remains to be elucidated. The combination of classical medical theories, including TCM and epigenetic modifications, which are emerging molecular biology concepts, provides new perspectives for antitumor therapy and warrants further exploration ( 54 , 55 ).…”

Section: The M6a Key Enzyme In the Development Of Crcmentioning

confidence: 99%

“…As the study of m6A methyltransferase is the most extensive and because 5-FU and OXA are the most commonly used chemotherapeutic agents in the treatment of CRC, the resistance mechanisms associated with m6A methylation were found to be highly dependent on the regulation of METTL3 ( 54 ) (as shown in Fig. 2 ).…”

Section: Mechanisms Of Chemoresistance In Crc Involving Key M6a Methy...mentioning

confidence: 99%

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Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review)

Shao,

Han,

Huang

et al. 2023

Int J Oncol

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RNA methylation modifications are closely linked to tumor development, migration, invasion and responses to various therapies. Recent studies have shown notable advancements regarding the roles of RNA methylation in tumor immunotherapy, the tumor microenvironment and metabolic reprogramming. However, research on the association between tumor chemoresistance and N6-methyladenosine (m6A) methyltransferases in specific cancer types is still scarce. Colorectal cancer (CRC) is among the most common gastrointestinal cancers worldwide. Conventional chemotherapy remains the predominant treatment modality for CRC and chemotherapy resistance is the primary cause of treatment failure. The expression levels of m6A methyltransferases, including methyltransferase-like 3 (METTL3), METTL14 and METTL16, in CRC tissue samples are associated with patients' clinical outcomes and chemotherapy efficacy. Natural pharmaceutical ingredients, such as quercetin, have the potential to act as METTL3 inhibitors to combat chemotherapy resistance in patients with CRC. The present review discussed the various roles of different types of key RNA methylation enzymes in the development of CRC, focusing on the mechanisms associated with chemotherapy resistance. The progress in the development of certain inhibitors is also listed. The potential of using natural remedies to develop antitumor medications that target m6A methylation is also outlined.

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“…Among the over 170 types of RNA modifications identified in eukaryotes [ 14 ], N6-methyladenosine (m 6 A) was the most commonly studied subtype, playing an important role in the progression of various malignant tumors [ 15 , 16 ]. In AML, abnormal levels of m6A modification have been shown to affect all aspects of the disease including leukemia stem cell self-renewal [ 17 ], therapeutic resistance [ 18 , 19 ], and leukemia cell proliferation [ 20 – 22 ] and poor survival [ 23 ]. In addition, other RNA modifications, including 2-O-methylation [ 24 ], pseudouridine (Ψ) [ 25 ], A-to-I editing [ 26 ], have emerged as effective modulators in leukaemogenesis.…”

Section: Introductionmentioning

confidence: 99%

METTL1 mediated tRNA m7G modification promotes leukaemogenesis of AML via tRNA regulated translational control

Zhao,

Xia,

Chen

et al. 2024

Exp Hematol Oncol

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Background RNA modifications have been proven to play fundamental roles in regulating cellular biology process. Recently, maladjusted N7-methylguanosine (m7G) modification and its modifiers METTL1/WDR4 have been confirmed an oncogene role in multiple cancers. However, the functions and molecular mechanisms of METTL1/WDR4 in acute myeloid leukemia (AML) remain to be determined. Methods METTL1/WDR4 expression levels were quantified using qRT-PCR, western blot analysis on AML clinical samples, and bioinformatics analysis on publicly available AML datasets. CCK-8 assays and cell count assays were performed to determine cell proliferation. Flow cytometry assays were conducted to assess cell cycle and apoptosis rates. Multiple techniques were used for mechanism studies in vitro assays, such as northern blotting, liquid chromatography-coupled mass spectrometry (LC–MS/MS), tRNA stability analysis, transcriptome sequencing, small non-coding RNA sequencing, quantitative proteomics, and protein synthesis measurements. Results METTL1/WDR4 are significantly elevated in AML patients and associated with poor prognosis. METTL1 knockdown resulted in reduced cell proliferation and increased apoptosis in AML cells. Mechanically, METTL1 knockdown leads to significant decrease of m7G modification abundance on tRNA, which further destabilizes tRNAs and facilitates the biogenesis of tsRNAs in AML cells. In addition, profiling of nascent proteins revealed that METTL1 knockdown and transfection of total tRNAs that were isolated from METTL1 knockdown AML cells decreased global translation efficiency in AML cells. Conclusions Taken together, our study demonstrates the important role of METTL1/WDR4 in AML leukaemogenesis, which provides a promising target candidate for AML therapy.

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Emerging roles of m6A RNA modification in cancer therapeutic resistance

Cited by 10 publications

References 186 publications

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

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

Targeting key RNA methylation enzymes to improve the outcome of colorectal cancer chemotherapy (Review)

METTL1 mediated tRNA m7G modification promotes leukaemogenesis of AML via tRNA regulated translational control

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