Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA

Zhang, Runjiao; Zhang, Yizhou; Guo, Fangzhen; Huang, Guannan; Zhao, Yan; Chen, Bingyu; Wang, Chang; Cui, Chengran; Shi, Yichun; Li, Sha; Cui, Huixian

doi:10.1038/s41420-022-01220-0

Cited by 9 publications

(2 citation statements)

References 48 publications

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“…To investigate whether m 6 A modification increases mRNA stability as previously reported (Zhang et al 2022a ), we conducted the mRNA stability using transcriptional repressor actinomycin D. The stability of p21 mRNA was significantly increased in DON-treated HT22 cells, and METTL3 knockdown significantly prevented DON-induced increase in p21 mRNA stability (Fig. 4 A).…”

Section: Resultssupporting

confidence: 51%

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Xu,

Zhao,

Feng

et al. 2024

Cell Biol Toxicol

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Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m6A methylation levels on the 3’UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6A readers YTHDF1 and IGF2BP1 are responsible for m6A-mediated increase in p21 mRNA stability. Meanwhile, 3’UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6A hypermethylated, and another m6A reader YTHDF2 binds to the m6A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases. Graphical abstract DON inhibits the proliferation of HT-22 cells. RNA m6A hypermethylation on the transcript of p21 enhances the mRNA stability in a YTHDF1- and IGF2BP1-dependent manner, which leads to the upregulation of p21. RNA m6A hypermethylation on the transcript of TRIM21 decreases the mRNA stability in a YTHDF2-dependent manner, which contributes to prevent p21 ubiquitin-mediated degradation. High expression of p21 contributes to inhibit cell proliferation.

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Section: Resultssupporting

confidence: 51%

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Xu,

Zhao,

Feng

et al. 2024

Cell Biol Toxicol

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“…METTL16, as a newly identified methyltransferase, was only reported to install m 6 A modifications on a few noncoding RNAs and pre-mRNAs in majorities of studies before 2018, such as MAT2A, U6 snRNA, and MALAT1 (Brown et al, 2016;Shima et al, 2017;Warda et al, 2017) but a subsequent study revealed that METTL16 could promote the translation of more than 4000 mRNA transcripts (Su et al, 2022) which implied that it had multiple undiscovered functions. Thereafter, multiple studies concentrated on the physiological function of METTL16 and discovered that it regulated the m 6 A modification on different mRNAs (Guo et al, 2022;Zhang et al, 2022Zhang et al, , 2023.…”

Section: Discussionmentioning

confidence: 99%

METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m⁶A‐dependent manner

Cheng

Tan

et al. 2023

Journal Cellular Physiology

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N6‐methyladenosine (m6A) is one of the main epitranscriptomic modifications that accelerates the progression of malignant tumors by modifying RNA. Methyltransferase‐like 16 (METTL16) is a newly identified methyltransferase that has been found to play an important oncogenic role in a few malignancies; however, its function in osteosarcoma (OS) remains unclear. In this study, METTL16 was found to be upregulated in OS tissues, and associated with poor prognosis in OS patients. Functionally, METTL16 substantially promoted OS cell proliferation, migration, and invasion in vitro and OS growth in vivo. Mechanistically, vacuolar protein sorting protein 33b (VPS33B) was identified as the downstream target of METTL16, which induced m6A modification of VPS33B and impaired the stability of the VPS33B transcript, thereby degrading VPS33B. In addition, VPS33B was found to be downregulated in OS tissues, VPS33B knockdown markedly attenuated shMETTL16‐mediated inhibition on OS progression. Finally, METTL16/VPS33B might facilitate OS progression through PI3K/AKT pathway. In summary, this study revealed an important role for the METTL16‐mediated m6A modification in OS progression, implying it as a promising target for OS treatment.

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The m⁶A‐independent role of epitranscriptomic factors in cancer

Bove,

Crepaldi,

Amin

et al. 2024

Intl Journal of Cancer

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Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N6‐methyladenosine (m6A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m6A system, has shown a dramatic impact on cancer development. However, the cellular localization of m6A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m6A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m6A that still represent an unexplored field. To date novel epigenetic drugs targeting m6A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco‐properties of m6A effectors beyond m6A is required. Here we will provide an overview of methylation‐independent functions of the m6A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.

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Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA

Cited by 9 publications

References 48 publications

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m⁶A‐dependent manner

The m⁶A‐independent role of epitranscriptomic factors in cancer

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Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA

Cited by 9 publications

References 48 publications

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

Deoxynivalenol induces m6A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro

METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m6A‐dependent manner

The m6A‐independent role of epitranscriptomic factors in cancer

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METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m⁶A‐dependent manner

The m⁶A‐independent role of epitranscriptomic factors in cancer