N6-methyladenosine regulates glycolysis of cancer cells through PDK4

Li, Zihan; Peng, Yanxi; Li, Jiexin; Chen, Zhuojia; Chen, Feng; Tu, Jian; Lin, Shuibin; Wang, Hongsheng

doi:10.1038/s41467-020-16306-5

Cited by 202 publications

(221 citation statements)

References 58 publications

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“…m6A plays critical roles in tumorigenesis and tumor progression [37] , [38] , [39] . Studies showed m6A can regulate the maturation and the ability of neoantigens presentation in immune cells, and regulate response to immunotherapy [ 5 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

Zhou

Zhang

et al. 2021

EBioMedicine

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Background: N6-methyladenosine (m6A) is the most abundant mRNA modification. Whether m6A regulators can determine tumor aggressiveness and risk of immune evasion in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Methods: An integrated model named "m6Ascore" is constructed based on RNA-seq data of m6A regulators in PDAC. Association of m6Ascore and overall survival is validated across several different datasets. Overlaps of m6Ascore and established molecular classifications of PDAC is examined. Immune infiltration, enriched pathways, somatic copy number alterations (SCNAs), mutation profiles and response to immune checkpoint inhibitors are compared between m6Ascore-high and m6Ascore-low tumors. Findings: m6Ascore is associated with dismal overall survival and increased tumor recurrence in PDAC as well as several other solid tumors including colorectal cancer and breast cancer. Basal-like (Squamous) PDAC has higher m6Ascore than that in the classical PDAC. Mechanism study showed m6Ascore-high tumors are characterized with reduced immune infiltration and T cells exhaustion. Meanwhile, m6Ascore is associated with genes regulating cachexia and chemoresistance in PDAC. Furthermore, distinct SCNAs patterns and mutation profiles of KRAS and TP53 are present in m6Ascore-high tumors, indicating immune evasion. m6Ascore-low tumors have higher response rates to immune checkpoint inhibitors (ICIs). Interpretation: These findings indicate m6Ascore can predict aggressiveness and immune evasion in pancreatic cancer. This model has implications for pancreatic cancer prognosis and treatment response to ICIs.

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Section: Discussionmentioning

confidence: 99%

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

Zhou

Zhang

et al. 2021

EBioMedicine

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“…14 m6A modification can influence mRNA decay, splicing, transport, localization, and translation. 15,16 In mammalian cells, m6A modification is dynamic, reversible, and catalyzed by m6A methyltransferases (METTL3, METTL14, and WTAP), also known as "writers". m6A demethylases (FTO and ALKBH5), also known as "erasers", are responsible for directly removing m6A modification of mRNA.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

Zhang

et al. 2021

Sig Transduct Target Ther

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N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.

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“…In addition, METTL3 was involved in m 6 A-regulated glycolysis, which was one of the critical hallmarks of tumor growth. METTL3 enhanced the stability of pyruvate dehydrogenase kinase 4 (PDK4) and HK2 mRNAs in a METTL3-m 6 A-YTHDF1-dependent manner, ultimately promoting tumor growth and chemoresistance [ 116 ].…”

Section: Mettl3 Mediates Tumorigenesis Via Rna Methylationmentioning

confidence: 99%

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

et al. 2021

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N6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

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N6-methyladenosine regulates glycolysis of cancer cells through PDK4

Cited by 202 publications

References 58 publications

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

An integrated model of N6-methyladenosine regulators to predict tumor aggressiveness and immune evasion in pancreatic cancer

HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

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