N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

Zou, Libin; Chen, Wenbin; Zhou, Xumin; Yang, Taowei; Luo, Junqi; Long, Zining; Wu, Jun; Lv, Daojun; Mao, Xiangming; Cen, Shengren

doi:10.1038/s41420-022-01003-7

Cited by 25 publications

(24 citation statements)

References 32 publications

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“…Nevertheless, there is little evidence about the role of FTO in PCa. Two recent studies stated that FTO inhibited the invasion and migration of PCa (36,54). In this study, we demonstrated that FTO expression was high in PCa and promoted cell proliferation in LNCaP and RWPE1 cells, which may be contrary to previous reported studies.…”

Section: Discussioncontrasting

confidence: 99%

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

zhao

wang

et al. 2023

Preprint

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Zinc-finger homeobox 3 (ZFHX3, also known as ATBF1) suppresses prostatic tumorigenesis; ZFHX3 is frequently found to have numerous deletions when found in human prostate cancer (PCa). However, the underlying molecular function of ZFHX3 during prostatic tumorigenesis is not well understood. N6-methyladenosine (m6A) modification in RNA plays a critical role in the development of cancers; however, the relationship between ZFHX3 and m6A modification is largely unknown in PCa. In this study, we found that ZFHX3 knockdown decreased total m6A levels through enhancing the transcriptional activity of FTO in PCa cells. Importantly, FTO inhibition suppressed cell proliferation and rescued the promoting function of ZFHX3 knockdown on cell proliferation. Through transcriptome sequencing and Me-RIP sequencing, we revealed that E2F2 and CDKN2C were the direct targets of FTO-mediated m6A modification and identified the role of E2F2 and CDKN2C in cell cycle arrest in FTO-depleted cells. Interestingly, ZFHX3 expression was in return regulated by FTO in m6A-dependent way. In vivo, we verified that FTO was upregulated and ZFHX3 was decreased in PCa patients and that a high level of ZFHX3 is indispensable for low FTO expression and is correlated with better patient survival. These findings establish a novel crosstalk mechanism between ZFHX3 and FTO in prostatic tumorigenesis.

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Section: Discussioncontrasting

confidence: 99%

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

zhao

wang

et al. 2023

Preprint

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“…As the first m6A demethylase identified to be dysregulated in various tumours, FTO is upregulated in pancreatic, gastric, and bladder cancers and promotes tumour growth and metastasis [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Reduced FTO expression in the liver, prostate, papillary thyroid, colorectal, and lung adenocarcinoma has been associated with poor prognosis [ 22 , 23 , 24 , 25 , 26 ]. Mechanistically, FTO demethylates downstream target mRNAs, affects m6A levels, and exerts pro- or anti-cancer effects [ 27 , 28 , 29 , 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

Sun¹,

Zhang²,

Bi³

et al. 2022

Cancers

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Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.

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“…m6A methylation modification plays an important role in maintaining stem cell metabolism [ 29 ], immune homeostasis [ 30 ], tumor immune microenvironment [ 31 ], immune suppression and escape [ 32 ], and other biological regulations. m6A methylation modification can also affect cell differentiation and proliferation by affecting the expression of transcription factors [ 33 , 34 ]. m6A methylation is modified by altering RNA folding and structure, which enhances mRNA export and translation [ 10 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis and Functional Characteristics of Differential Expression of N6-Methyladenosine Methylation Modification in the Whole Transcriptome of Rheumatoid Arthritis

Wan

Liu

Huang

et al. 2022

Mediators of Inflammation

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N6-methyladenosine (m6A) modification is the most prevalent chemical modification in eukaryotic mRNA and is associated with the development of various immune diseases. However, the role of m6A methylation in rheumatoid arthritis (RA) development is unclear. We preliminarily explored the role of m6A methylation-related mRNAs in RA for its clinical application. The discovery of m6A methylation-modifying genes in this study may provide a fresh perspective on the development of drugs for RA treatment. High-throughput sequencing combined with methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing were used to assess whole-transcriptome m6A modifications in the synovium of patients with RA. The relationship between m6A-modified target genes and RA inflammation and macrophages was determined. The expression of the m6A-modified significant transcript-enriched inflammatory signaling pathway was assessed through animal experiments. Differentially expressed m6A genes were correlated with macrophage activation involved in immune response, vascular endothelium, MAPK signaling pathway, PI3K − Akt signaling pathway, and other inflammatory processes. Furthermore, combined analysis with m6A-seq and RNA-seq revealed 120 genes with significant changes in both m6A modification and mRNA expression. We selected the top 3 candidate mRNAs that were upregulated and downregulated simultaneously. The expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) mRNA and protein in RA patients was lower than that in healthy control (HC). SHC-binding protein 1 (SHCBP1) and neurexophilin-3 (NXPH3) mRNA expressions were increased in RA patients. The expression of M1 macrophages was increased in RA patients. RA markers are such as rheumatoid factor (RF) and peptide containing citrulline (CCP). Further animal experiments showed that the expression of synovial MAPK, PI3K, and Akt1 proteins in the RA model was increased, and the PTEN, p-PTEN protein expression was decreased. PI3K, Akt1, PTEN, and p-PTEN were correlated to RA joint inflammation. This study revealed a unique pattern of differential m6A methylation modifications in RA and concluded that m6A modification is related to the occurrence of RA synovial inflammation.

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N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

Cited by 25 publications

References 32 publications

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation

FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

Comprehensive Analysis and Functional Characteristics of Differential Expression of N6-Methyladenosine Methylation Modification in the Whole Transcriptome of Rheumatoid Arthritis

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