The Role of RNA Methyltransferase METTL3 in Normal and Malignant Hematopoiesis

Wu, Xia; Wu, Ye; Gong, Yuping

doi:10.3389/fonc.2022.873903

Cited by 17 publications

(14 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The m 6 A writer METTL3, a potential therapeutic target for AML treatment, has recently been reported to promote the initiation and maintenance of AML (15). However, its regulatory mechanisms in AML remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Although accumulating evidence has demonstrated that METTL3 plays critical roles in promoting AML progression as an m 6 A methyltransferase (15,21), it has not been reported whether the E3 ubiquitin ligase can mediate the ubiquitination of METTL3 in AML. To identify METTL3-related E3 ligases, we rst expressed Flag-METTL3 in AML cells and performed mass spectrometric analysis of METTL3-immunoprecipitated complexes from AML cells.…”

Section: Rnf113a Functions As An E3 Ubiquitin Ligase To Mediate Circ_...mentioning

confidence: 99%

“…N6-methyladenosine (m 6 A) has been proven to in uence RNA functions and play crucial roles in hematopoietic stem cell (HSC) biology and leukemic transformation (8-14). METTL3, the core methyltransferase involved in m 6 A modi cation, has been reported to play signi cant roles in normal hematopoiesis or hematological malignancies, including AML, acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and lymphoma (15,16). Elevated expression of METTL3 in AML has been shown to promote proliferation and chemoresistance and decrease the apoptosis of leukemia cells (15).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

Yang

Han

et al. 2022

Preprint

View full text Add to dashboard Cite

Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML), but its regulatory mechanism remains unclear. Herein, we identify a novel m6A modification-related circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contributes to a poor prognosis. We find that the expression of Circ_0001187 is regulated by the modification of DNA methylation and histone acetylation, and its biogenesis is meditated by splicing factor EIF4A3. Knockdown of Circ_0001187 significantly promotes the proliferation and inhibits the apoptosis of AML cells in vitro and in vivo, while overexpression of Circ_0001187 exerts the opposite effects. Moreover, we prove that Circ_0001187 enhances METTL3 protein degradation, which further decreases mRNA m6A modification in AML cells. Mechanistically, Circ_0001187 sponges miR-499a-5p to enhance the expression RNF113A. And RNF113A functions as an E3 ubiquitin ligase to mediate METTL3 ubiquitin/proteasome-dependent degradation by K48-linked polyubiquitin chains. Collectively, our findings highlight the potential clinical implications of Circ_0001187 as a key tumor suppressor of AML via the miR-499a-5p/RNF113A/METTL3 pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Rnf113a Functions As An E3 Ubiquitin Ligase To Mediate Circ_...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

Yang

Han

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Further, circIGF2BP3 is overexpressed and compromises anti-tumor immunity in NSCLC. METTL3 and METTL14 are composed of a stable methyltransferase complex (MTC) in a 1:1 ratio and exerts a methylation function ( 128 ). Promoting m6A levels in the circIGF2BP3 transcript in a METTL3-dependent manner could enhance the circularization of circIGF2BP3.…”

Section: Interaction Between Ups and Regulatory Ncrnas In Nsclcmentioning

confidence: 99%

The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer

Sun

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

Lung cancer (LC) remains the leading cause of cancer-related deaths worldwide, with extremely high morbidity and mortality rates. Non-small cell lung cancer (NSCLC) is the most critical type of LC. It seriously threatens the life and health of patients because of its early metastasis, late clinical symptoms, limited early screening methods, and poor treatment outcomes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), participate in cell proliferation, metastasis, and chemoresistance. Several previous studies have proven that ncRNAs are vital regulators of tumorigenesis. Ubiquitination plays the most crucial role in protein post-translational modification (PTM). Deubiquitination and ubiquitination form a homeostasis. In summary, ubiquitination and deubiquitination play essential roles in mediating the degradation or overexpression of a range of crucial proteins in various cancers. A growing number of researchers have found that interactions between ncRNAs and ubiquitination (or deubiquitination) play a crucial role in NSCLC. This review presents several typical examples of the important effects of ncRNAs and ubiquitination (or deubiquitination) in NSCLC, aiming to provide more creative ideas for exploring the diagnosis and treatment of NSCLC.

show abstract

“…METTL3 is the most common and most extensively studied methyltransferase of m6A. m6A modifications significantly modulate RNA stability, localization, transport, splicing and translation ( 18 ). METTL3 also plays an integral role in the development and progression of various of tumors.…”

Section: Introductionmentioning

confidence: 99%

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

Chen

Wang

et al. 2023

Oncol Rep

View full text Add to dashboard Cite

The present study aimed to explore the potential roles of the methyltransferase-like 3 (METTL3)-mediated methylation of RAS related (RRAS) mRNA in the tumorigenesis and development of bladder cancer (BCa). For this purpose, the relative expression levels of METTL3 in BCa specimens and cell lines were measured using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. The association between the METTL3 expression level and the clinical characteristics of patients with BCa was analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis databases. Cellular experiments were performed to confirm the effects of METTL3 on the proliferative, migratory and invasive capacities of BCa cells. RT-qPCR, western blot analysis, methylated RNA immunoprecipitation (MeRIP)-qPCR and dual-luciferase report assays were utilized to verify the METTL3/RRAS/YTH N 6 -methyladenosine (m6A) RNA binding protein 2 (YTHDF2) regulatory axis in BCa. The results revealed that METTL3 expression was markedly increased in BCa specimens and cell lines, and was associated with poor clinical characteristics of patients with BCa. In vitro and in vivo assays demonstrated that the silencing of METTL3 markedly suppressed the proliferative, migratory and invasive capacities of BCa cells. MeRIP-PCR and dual-luciferase report assays indicated that METTL3 could bind to the m6A sites of RRAS mRNA and suppress the transcriptional activity of RRAS. YTHDF2 could recognize the m6A sites of RRAS and mediate RRAS degradation. On the whole, the findings of the present study reveal the pivotal role of METTL3-catalyzed m6A modification in BCa tumorigenesis and development. The change could facilitate BCa tumor growth and metastasis by suppressing RRAS expression in an m6A YTHDF2-dependent manner. Targeting the METTL3/RRAS/YTHDF2 regulatory axis may thus prove to be a promising strategy for the diagnosis and therapy of BCa.

show abstract

The Role of RNA Methyltransferase METTL3 in Normal and Malignant Hematopoiesis

Cited by 17 publications

References 79 publications

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway

The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer

METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

Contact Info

Product

Resources

About