METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Xu, Yiming; Lv, Dandan; Yan, Chao; Su, Hua; Zhang, Xue; Shi, Yandong; Ying, Kejing

doi:10.1186/s12935-021-02433-6

Cited by 77 publications

(63 citation statements)

References 52 publications

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“…Consistent with our results, Lin et al also showed that knockout of METTL3 in pre-osteoblastic MC3T3-E1 cells attenuated the level of ferroptosis [44]. However, Xu et al revealed that METTL3-mediated m 6 A modification of SLC7A11 mRNA was read by YTHDF1, which promoted the translation of SLC7A11 mRNA to inhibit lung adenocarcinoma cell ferroptosis [45]. The possible reason for this opposite scenario is that there are differences in the energy metabolism of tumor cells (aerobic glycolysis) and normal cells (mitochondrial oxidative phosphorylation) [46].…”

Section: Discussionsupporting

confidence: 90%

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Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Li¹,

Yi²,

He³

et al. 2022

Int. J. Biol. Sci.

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A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the β-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m 6 A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin-and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m 6 A RNA methylation is a potential novel strategy for the treatment of AD.

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Section: Discussionsupporting

confidence: 90%

“…On the other hand, the m 6 A methylated mRNAs may have different fates when recognized by different readers. For example, the mRNA of SLC7A11 is recognized by YTHDC2 to promote its degradation [32], while the recognition by YTHDF1 promotes its translation [45].…”

Section: Discussionmentioning

confidence: 99%

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Li¹,

Yi²,

He³

et al. 2022

Int. J. Biol. Sci.

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“…Studies have found that m 6 A modification enhances ferroptosis in stellate cells by stabilizing BECN1mRNA to trigger autophagy activation [ 16 ]. Other studies have found that METTL3-mediated m 6 A methylation can stabilize SLC7A11mRNA and accelerate translation, thereby inhibiting ferroptosis and accelerating the proliferation of lung cancer cells [ 7 ]. In this study, we also found that increased m 6 A methylation levels upregulated FUS expression and inhibited ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Erastin, a ferroptosis inducer, and second-generation antiandrogen RSL3 therapy phenomenally reduced CRPC growth and migration with no adverse effects [ 5 ]. OIP5-AS1 can regulate the expression of ferroptosis marker SLC7A11 through miR-128-3p, thus accelerating the progression of PRAD and ferroptosis resistance [ 7 ]. In addition, studies have found that flubendazole can induce P53 expression, downregulate ferroptosis markers SLC7A11 and GPX4 levels, and play an anti-CRPC proliferation and proapoptotic effect [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

mRNA-Modified FUS/NRF2 Signalling Inhibits Ferroptosis and Promotes Prostate Cancer Growth

Wang¹,

Yu²,

Wang³

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. Regarding the imperfect mechanism of occurrence and development of prostate adenocarcinoma (PRAD), this study investigated mRNA-modified FUS/NRF2 signalling to inhibit ferroptosis and promote prostate adenocarcinoma growth. Methods. Bioinformatics analysis was used to obtain the expression of FUS and its mRNA modification in PRAD. The expression of FUS in prostate cells (CRPC) and the level of m6A methylation modification, ferroptosis (P53 and GPX4), apoptosis (Caspase3), ferroptosis (P53 and GPX4), and apoptosis (Caspase3) in CRPC after ferroptosis inducer Erastin, ferroptosis inhibitor, and FUS knockdown were detected. Autophagy (LC3B), oxidative stress (GSH and ROS), and expression of NRF2/HO-1 pathway are indicators. Results. FUS was highly expressed in PRAD and phenomenally reduced the survival rate of patients. After knocking down FUS, the level of m6A methylation was significantly reduced, and the expressions of ferroptosis markers P53 and GPX4 were phenomenally reduced, while the levels of apoptosis and autophagy markers Caspase3 and LC3B remained unchanged. Upregulated and NRF2/HO-1 pathway indicators were upregulated. It shows that m6A methylation modification is reduced when FUS is the low expression, inhibits the expression of P53 and GPX4, downregulates GSH, upregulates ROS, activates the NRF2/HO-1 pathway, and promotes ferroptosis to inhibit the occurrence of RPAD. Conclusions. The increase of m6A methylation modification can increase the expression of FUS, thereby promoting the expression of P53 and GPX4, upregulating GSH, downregulating ROS, inhibiting the NRF2/HO-1 pathway, inhibiting ferroptosis, and promoting the growth of PRAD.

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“…Cell ferroptosis, a novel form of programmed cell death. The highly expressed METTL3 in LUAD can promote LUAD cell proliferation and inhibit ferroptosis, and its molecular mechanism is that METTL3-mediated m6A modification enhances the stability of SLC7A11 mRNA and promotes its translation ( Xu et al, 2022 ). Metabolic reprogramming, known as the Warburg effect, is considered a key hallmark of cancer, including lung cancer.…”

Section: Part 2: the Role Of M6a Modification In Cancermentioning

confidence: 99%

The Role of m6A RNA Methylation in Cancer: Implication for Nature Products Anti-Cancer Research

et al. 2022

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N6-methyladenosine (m6A) RNA methylation is identified as the most common, abundant and reversible RNA epigenetic modification in messenger RNA (mRNA) and non-coding RNA, especially within eukaryotic messenger RNAs (mRNAs), which post-transcriptionally directs many important processes of RNA. It has also been demonstrated that m6A modification plays a pivotal role in the occurrence and development of tumors by regulating RNA splicing, localization, translation, stabilization and decay. Growing number of studies have indicated that natural products have outstanding anti-cancer effects of their unique advantages of high efficiency and minimal side effects. However, at present, there are very few research articles to study and explore the relationship between natural products and m6A RNA modification in tumorigenesis. m6A is dynamically deposited, removed, and recognized by m6A methyltransferases (METTL3/14, METTL16, WTAP, RBM15/15B, VIRMA, CBLL1, and ZC3H13, called as “writers”), demethylases (FTO and ALKBH5, called as “erasers”), and m6A-specific binding proteins (YTHDF1/2/3, YTHDC1/2, IGH2BP1/2/3, hnRNPs, eIF3, and FMR1, called as “readers”), respectively. In this review, we summarize the biological function of m6A modification, the role of m6A and the related signaling pathway in cancer, such as AKT, NF-kB, MAPK, ERK, Wnt/β-catenin, STAT, p53, Notch signaling pathway, and so on. Furthermore, we reviewed the current research on nature products in anti-tumor, and further to get a better understanding of the anti-tumor mechanism, thus provide an implication for nature products with anti-cancer research by regulating m6A modification in the future.

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METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Cited by 77 publications

References 52 publications

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

mRNA-Modified FUS/NRF2 Signalling Inhibits Ferroptosis and Promotes Prostate Cancer Growth

The Role of m6A RNA Methylation in Cancer: Implication for Nature Products Anti-Cancer Research

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