m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Huang, Weimei; Li, Zhixun; Wu, Yinghui; Shi, Zhiling; Mi, Jinglin; Hu, Kai; Wang, Rensheng

doi:10.1016/j.tranon.2022.101576

Cited by 45 publications

(39 citation statements)

References 32 publications

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“…Radiotherapy not only causes various modes of cell death, including apoptosis, necrosis, and pyroptosis, but also induces ferroptosis, which play an important role in the treatment of malignant tumors. It has been reported that erastin, a ferroptosis inducer, decreases radio‐resistance of non‐small cell lung cancer cells partially by inducing GPX4‐mediated ferroptosis [69]; M6A demethylase FTO enhances radiotherapy resistance in nasopharyngeal carcinoma by promoting Otub1‐mediated anti‐ferroptosis [70]; Ye et al [71] reported that ferroptosis inducers enhanced the antitumor effect of radiation in HT1080 cells. Silencing FANCD2 inhibited the growth of a SHH subgroup of MB cells in vitro and in vivo , suggesting that silencing FANCD2 might enhance the sensitivity of SHH‐MB cells to radiotherapy by increased ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single‐cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK‐8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2‐related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH‐MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH‐MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH‐MB cells and sensitized SHH‐MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH‐MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH‐MB cell‐derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH‐MB and silencing FANCD2 could sensitize SHH‐MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

Zhou,

Wang,

et al. 2024

The Journal of Pathology

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“…It is reported that FTO overexpression impairs dihydroartemisinin‐triggered ferroptotic events in hepatic stellate cells (Shen et al, 2022). As well, FTO is demonstrated to erase m6A methylation of OTU domain, ubiquitin aldehyde binding 1 to inhibit radiation‐induced ferroptosis of nasopharyngeal carcinoma cells (Huang et al, 2023). Herein, we demonstrated that FTO overexpression resulted in the demethylation and instability of MDM2, thus affecting the downstream TLR4/SLC7A11/GPX4 signaling axis and ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

N6 methyladenosine eraser FTO suppresses Staphylococcus aureus‐induced ferroptosis of bone marrow mesenchymal stem cells to ameliorate osteomyelitis through regulating the MDM2/TLR4/SLC7A11 signaling pathway

Song,

Lv,

et al. 2024

Cell Biology International

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Osteomyelitis is a bone destructive inflammatory disease caused by infection. Ferroptosis is closely related to multiple inflammatory diseases, but the role of ferroptosis in Staphylococcus aureus (SA)‐induced osteomyelitis remains unknown. In the present study, we found that SA treatment promoted the accumulation of iron, Fe2+, lipid peroxide, and malondialdehyde, increased TFRC and reduced FTH1 and GPX4 to trigger ferroptosis in rat bone marrow mesenchymal stem cells (BMSCs). Interestingly, increased level of N6 methyl adenosine (m6A) modification along with decreased expression level of m6A eraser FTO were observed in SA‐induced BMSCs, while upregulating FTO alleviated SA‐triggered ferroptosis and protected cell viability in BMSCs. Mechanistically, MDM2 was identified as a target of FTO‐mediated m6A demethylation, and FTO upregulation promoted MDM2 instability to downregulated TLR4 signal and elevate the expression of SLC7A11 and GPX4 in SA‐induced BMSCs. Functional recovery experiments verified that overexpressing MDM2 or TLR4 reversed the inhibiting effect of FTO upregulation on ferroptosis in SA‐treated BMSCs. Additionally, FTO upregulation restrained ferroptosis and pathological damage to bone tissue in SA‐induced osteomyelitis model rats. Altogether, m6A eraser FTO alleviates SA‐induced ferroptosis in osteomyelitis models partly through inhibiting the MDM2‐TLR4 axis.

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“…30 In combination with the ferroptosis activator erastin, FB23-2 also alters tumor responsiveness to radiotherapy on nasopharyngeal carcinoma (NPC) cell carrying PDX mouse models. 31 Dac51, which inhibited FTO, significantly impaired uterine leiomyosarcoma (uLMS) proliferation via cell cycle arrest and increased the expression of CDKN1A, thereby rewiring several critical pathways and resulting in suppressed uLMS phenotype. 32 These findings show that suppressing tumor growth through inhibiting FTO demethylase is highly feasible (Table 1).…”

Section: Application Of Our Inhibitors In Rna Epigeneticsmentioning

confidence: 99%

“…As a highly potent FTO inhibitor, FB23-2 suppresses RAS-mediated oncogenic translation and tumorigenesis of pancreatic cancer . In combination with the ferroptosis activator erastin, FB23-2 also alters tumor responsiveness to radiotherapy on nasopharyngeal carcinoma (NPC) cell carrying PDX mouse models . Dac51, which inhibited FTO, significantly impaired uterine leiomyosarcoma (uLMS) proliferation via cell cycle arrest and increased the expression of CDKN1A , thereby rewiring several critical pathways and resulting in suppressed uLMS phenotype .…”

Section: Chemical Intervention In M6a Modificationmentioning

confidence: 99%

Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins

Huang,

Xia,

Dong

et al. 2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Epigenetics is brought to RNA, introducing a new dimension to gene expression regulation. Among numerous RNA modifications, N 6 -methyladenosine (m 6 A) is an abundant internal modification on eukaryote mRNA first identified in the 1970s. However, the significance of m 6 A modification in mRNA had been long neglected until the fat mass and obesity-associated (FTO) enzyme was identified as the first m 6 A demethylase almost 40 years later. The m 6 A modification influences nearly every step of RNA metabolism and thus broadly affects gene expression at multiple levels, playing a critical role in many biological processes, including cancer progression, metastasis, and immune evasion. The m 6 A level is dynamically regulated by RNA epigenetic machinery comprising methyltransferases such as methyltransferase-like protein 3 (METTL3), demethylases FTO and AlkB human homologue 5 (ALKBH5), and multiple reader proteins. The understanding of the biology of RNA epigenetics and its translational drug discovery is still in its infancy. It is essential to further develop chemical probes and lead compounds for an in-depth investigation into m 6 A biology and the translational discovery of anticancer drugs targeting m 6 A modifying oncogenic proteins.In this Account, we present our work on the development of chemical inhibitors to regulate m 6 A in mRNA by targeting the FTO demethylase, and the elucidation of their mode of action. We reported rhein to be the first substrate competitive FTO inhibitor. Due to rhein's poor selectivity, we identified meclofenamic acid (MA) that selectively inhibits FTO compared with ALKBH5. Based on the structural complex of MA bound with FTO, we designed MA analogs FB23-2 and Dac51, which exhibit significantly improved activities compared with MA. For example, FB23-2 is specific to FTO inhibition in vitro among over 400 other oncogenic proteins, including kinases, proteases, and DNA and histone epigenetic proteins. Mimicking FTO depletion, FB23-2 promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cells and inhibits the progression of primary cells in xenotransplanted mice. Dac51 treatment impairs the glycolytic activity of tumor cells and restores the function of CD8 + T cells, thereby inhibiting the growth of solid tumors in vivo. These FTO inhibitors were and will continue to be used as probes to promote biological studies of m 6 A modification and as lead compounds to target FTO in anticancer drug discovery.Toward the end, we also include a brief review of ALKBH5 demethylase inhibitors and METTL3 methyltransferase modulators.Collectively, these small-molecule modulators that selectively target RNA epigenetic proteins will promote in-depth studies on the regulation of gene expression and potentially accelerate anticancer target discovery.

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m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Cited by 45 publications

References 32 publications

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

N6 methyladenosine eraser FTO suppresses Staphylococcus aureus‐induced ferroptosis of bone marrow mesenchymal stem cells to ameliorate osteomyelitis through regulating the MDM2/TLR4/SLC7A11 signaling pathway

Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins

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m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis

Cited by 45 publications

References 32 publications

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

N6 methyladenosine eraser FTO suppresses Staphylococcus aureus‐induced ferroptosis of bone marrow mesenchymal stem cells to ameliorate osteomyelitis through regulating the MDM2/TLR4/SLC7A11 signaling pathway

Chemical Inhibitors Targeting the Oncogenic m6A Modifying Proteins

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Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins