Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

Cai, Yin; Feng, Rui; Lü, Tianshi; Chen, Xiaomin; Zhou, Xiangxiang; Wang, Xin

doi:10.1186/s40364-021-00278-9

Cited by 32 publications

(22 citation statements)

References 125 publications

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“…For example, methyltransferase-like 3 (METTL3) and METTL14 can form a steady heterodimer complex. They shape the m 6 A methyltransferase complex (MTC) along with their accessory factors Wilms tumor 1-associated protein (WTAP), Vir like m 6 A methyltransferase associated (VIRMA/KIAA1429), RNA binding motif protein (RBM) 15/15b, zinc finger CCCH-Type containing 13 (ZC3H13), and HAKAI [ 5 – 10 ]. These factors act as m 6 A "writers" and collectively catalyze m 6 A modification.…”

Section: Introductionmentioning

confidence: 99%

m6A binding protein YTHDF2 in cancer

2022

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YT521-B homology domain family member 2 (YTHDF2) is an N6-methyladenosine (m6A)-binding protein that was originally found to regulate the stability of mRNA. Growing evidence has shown that YTHDF2 can participate in multifarious bioprocesses, including embryonic development, immune response, and tumor progression. Furthermore, YTHDF2 is closely associated with the proliferation, apoptosis, invasion, and migration of tumor cells, suggesting its significant role in cancers. YTHDF2 primarily relies on m6A modification to modulate signaling pathways in cancer cells. However, the expression and function of YTHDF2 in human malignancies remain controversial. Meanwhile, the underlying molecular mechanisms of YTHDF2 have not been elucidated. In this review, we principally summarized the biological functions and molecular mechanisms of YTHDF2 in tumors and discussed its prognostic and therapeutic values.

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Section: Introductionmentioning

confidence: 99%

m6A binding protein YTHDF2 in cancer

2022

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“…METTL3 is a methyltransferase that can modulate the initiation and progression of various types of cancers [ 27 ]. To determine the function of METTL3 in ESCA, the METTL3 expression pattern in cancer samples and normal samples was analyzed by the Starbase website ( http://starbase.sysu.edu.cn/ ).…”

Section: Resultsmentioning

confidence: 99%

“…METTL3 can function as a regulator for chief oncogenes to facilitate tumorigenesis and tumor progression [ 27 ]. Initially, our findings identified an increased concentration of METTL3 in 162 ESCA samples, ESCA tissues, and cells.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of methyltransferase like 3 in epithelial-mesenchymal transition process, invasion, and metastasis in esophageal cancer

et al. 2021

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Methyltransferase like 3 (METTL3) has been identified to serve as a definitive inducer in cancer progression. This study sought to analyze the regulatory mechanism of METTL3 in epithelial-mesenchymal transition (EMT), invasion, and metastasis in esophageal cancer (ESCA). The METTL3 expressions in cancer tissues and cells were detected with extensive analysis of its correlation with clinical baseline data. The cells were transfected with sh-RNA-METTL3 and microRNA (miR)-20a-5p mimic, followed by evaluation of invasion, migration, and EMT. The N6-methyladenosine (m6A) level and enrichment of DiGeorge Critical Region 8 (DGCR8) and m6A were observed. The binding relationship between miR-20a-5p and Nuclear Factor I-C (NFIC) was verified, followed by Pearson correlation analysis. A subcutaneous tumor formation assay was conducted prior to observation of lung metastases. Our results revealed that METTL3 was highly expressed in ESCA patients and associated with severe lymph node involvement and distant metastasis. METTL3 downregulation radically inhibited the invasiveness, migration, and EMT. METTL3 elevated the miR-20a-5p expression via improving m6A modification. METTL3 inhibition downregulated the miR-20a-5p expression. Moreover, miR-20a-5p upregulation facilitated ESCA cell invasiveness and migration by targeting NFIC transcription. METTL3 inhibition suppressed tumor growth and lung metastasis in vivo . Overall, METTL3 promoted m6A modification and the binding of DGCR8 to miR-20a-5p to further elevate the miR-20a-5p expression and inhibit NFIC transcription, thus promoting EMT, invasion and migration.

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“…METTL3 is the master component of the writer complex and plays key roles in regulating gene expression [ 32 ]. METTL3 was reported to display a dual role as both an oncogene and a tumor suppressor [ 39 ]. Previous publications have reported that METTL3 is downregulated in PTC and functions as a suppressor by regulating neutrophil infiltration, which was in line with our observations [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

METTL3-mediated m6A modification of STEAP2 mRNA inhibits papillary thyroid cancer progress by blocking the Hedgehog signaling pathway and epithelial-to-mesenchymal transition

et al. 2022

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Papillary thyroid cancer (PTC) is a common endocrine system malignancy all over the world. Aberrant expression of six transmembrane epithelial antigen of the prostate 2 (STEAP2) has been functionally associated with cancer progression in many cancers. Nevertheless, its biological function in PTC is still unclear. Here, we found that PTC tissues had preferentially downregulated STEAP2 as compared with noncancerous tissues. Low STEAP2 expression correlated with aggressive clinicopathological characteristics and dismal prognosis in patients with PTC. We performed gain- and loss-of-function experiments, including cell proliferation assay (Cell Counting Kit-8 assay), EdU (5-ethynyl-2′-deoxyuridine) and colony formation assays, transwell migration, and invasion assays, and constructed a nude mouse xenograft tumor model. The results demonstrated that STEAP2 overexpression inhibited PTC cell proliferation, migration, and invasion in vitro and inhibited lung metastasis and tumorigenicity in vivo. Conversely, silencing STEAP2 yielded the opposite results in vitro. Mechanistically, bioinformatics analysis combined with validation experiments identified STEAP2 as the downstream target of methyltransferase-like 3 (METTL3)-mediated N6-methyladenosine (m6A) modification. METTL3 stabilized STEAP2 mRNA and regulated STEAP2 expression positively in an m6A-dependent manner. We also showed that m6A-mediated STEAP2 mRNA translation initiation relied on a pathway dependent on the m6A reader protein YTHDF1. Rescue experiments revealed that silencing STEAP2 partially rescued the tumor-suppressive phenotype induced by METTL3 overexpression. Lastly, we verified that the METTL3–STEAP2 axis functions as an inhibitor in PTC by suppressing epithelial–mesenchymal transition and the Hedgehog signaling pathway. Taken together, these findings strongly suggest that METTL3-mediated STEAP2 m6A modification plays a critical tumor-suppressive role in PTC progression. The METTL3–STEAP2 axis may be a potential therapeutic molecular target against PTC.

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Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

Cited by 32 publications

References 125 publications

m6A binding protein YTHDF2 in cancer

m6A binding protein YTHDF2 in cancer

Mechanism of methyltransferase like 3 in epithelial-mesenchymal transition process, invasion, and metastasis in esophageal cancer

METTL3-mediated m6A modification of STEAP2 mRNA inhibits papillary thyroid cancer progress by blocking the Hedgehog signaling pathway and epithelial-to-mesenchymal transition

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