RNA N6-methyladenosine demethylase FTO regulates PD-L1 expression in colon cancer cells

Tsuruta, Nobuhiro; Tsuchihashi, Kazufumi; Ohmura, Hirofumi; Yamaguchi, Kyoko; Ito, Mamoru; Ariyama, Hiroshi; Kusaba, Hitoshi; Akashi, Koichi; Baba, Eishi

doi:10.1016/j.bbrc.2020.06.153

Cited by 68 publications

(51 citation statements)

References 33 publications

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“…m6A-binding protein YTHDF1 mediates m6A methylation, where the therapeutic efficacy of anti-PD-1 therapy is enhanced in YTHDF1-knockout mice [ 113 ]. Fat mass and obesity-associated protein (FTO) demethylates m6A, depleting FTO downregulated IFN-γ-induced PD-L1 expression in colon cancer [ 114 ].…”

Section: Regulation Of Pd-l1 and Ctla-4 At Rna Levelmentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

299

168

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The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

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Section: Regulation Of Pd-l1 and Ctla-4 At Rna Levelmentioning

confidence: 99%

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Zhang

Dai

et al. 2021

J Exp Clin Cancer Res

299

168

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“…FTO was demonstrated to rectify PD-L1 expression and promote immune evasion [47,48]. However, the roles of other m6A regulators in immune escape remain unclear, and the deepen understanding of m6A RNA methylation may explain the dissatisfactory effect of immune check point inhibitors in certain cancers.…”

Section: Discussionmentioning

confidence: 99%

Expression Status and Prognostic Roles of m6A-related Genes in Multiple Myeloma: YTHDF2 as the independent prognostic factor

Li¹,

Shen²,

Wu³

et al. 2021

Preprint

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Background: N6-methyladenosine is the most abundant RNA modification, which plays a prominent role in multiple biology processes, including tumorigenesis. Multiple myeloma (MM) is the second most frequent hematological cancer. However, the expression status and value of m6A-related genes in multiple myeloma remain elusive.Methods: m6A-related gene expression data and clinical information of MM patients were obtained from the Gene Expression Omnibus (GEO) database. Based on differentially expressed analysis, protein-protein interaction (PPI) analysis, Pearson correlation analysis, Kaplan-Meier survival analysis and Cox regression analysis, the prognostic m6A-associated genes were identified. The receiver operation characteristic (ROC) curves were used to verify the prognostic and diagnostic efficiency. The molecular mechanisms were investigated by differentially expressed mRNA and microRNA analyses with the help of online database ENCORI and POSTAR.Results: Among 22 m6A-related genes, HNRNPC, RBM15B, RBM15, YTHDF3, YTHDF2, HNRNPA2B1 and IGF2BP2 were significantly upregulated, while ZC3H13, FTO, IGF2BP3, ALKBH5 and YTHDC1 were significantly downregulated in MM patients. The high expression of HNRNPC, HNRNPA2B1, YTHDF2 and the low expression of ZC3H13 were associated with adverse survival. Furthermore, the expression level of YTHDF2 was the independent prognostic factor of MM. ROC curves suggested the great prediction performance for MM patients. Differentially expressed mRNA and microRNA analyses indicated the probable involvement of miR-205/YTHDF2/EGR1 axis.Conclusions: Our study first systematically analyzed the expression status of m6A-related genes in multiple myeloma, identified HNRNPC, HNRNPA2B1, YTHDF2 and ZC3H13 that could be the potential prognostic biomarkers, especially YTHDF2, which may be implicated in the miR-205/YTHDF2/EGR1 axis.

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“…FTO is upregulated in CRC and reduces the m6A modification, which can active MYC to induce carcinogenesis and regulate PD-L1 to affect immune escape. 50 , 51 Besides, low expression of FTO was related to polyubiquitin binding, mRNA 3ʹ end processing, transcription elongation from RNA polymerase II and poor overall survival. 52 , 53 In addition, diminished FTO expression is the key factor for promoting the cancer stem-like traits in CRC, including sphere forming, in vivo tumorigenicity, and chemoresistance.…”

Section: Role Of the Fto Gene In Digestive System Cancersmentioning

confidence: 99%

“… [ 49 ] Colorectal cancer Oncogene Up PD-L1 FTO mediated m6A regulated PD-L1 expression that might affect a therapeutic response to immunotherapy. [ 50 ] Colorectal cancer Oncogene Up MYC MiR-96 could potentially stimulate malignancy and aggressiveness of CRC by activating AMPKα2-mediated FTO/MYC. [ 51 ] Pancreatic cancer Oncogene Up c-MYC FTO enhanced stability of MYC and bHLH via decreasing m6A level.…”

Section: Role Of the Fto Gene In Digestive System Cancersmentioning

confidence: 99%

Emerging Roles of N6-Methyladenosine Demethylases and Its Interaction with Environmental Toxicants in Digestive System Cancers

Liu

Yang

Zhang

et al. 2021

CMAR

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Digestive system cancers are common cancers with high cancer deaths worldwide. They have become a major threat to public health and economic burden. As one of the most universal RNA modifications in eukaryotes, the N6-methyladenosine (m6A) modification is involved in the occurrence, development, prognosis, and treatment response of various cancers, including digestive system cancers. M6A demethylases shape the m6A landscape dynamically, playing important roles in cancers. In addition, accumulating evidence reveal that many environmental toxicants are the established risk factors for digestive system cancers and associated with m6A modification. In this review, we summarize the multiple functions of M6A demethylases (fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and AlkB homolog 3 (ALKBH3)) in digestive system cancers, which are aberrantly expressed and affect cancer progression. We also discuss the potential roles of m6A demethylases in the assessment of environmental exposure, the signature for prevention and diagnosis of digestive system cancers.

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RNA N6-methyladenosine demethylase FTO regulates PD-L1 expression in colon cancer cells

Cited by 68 publications

References 33 publications

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

Expression Status and Prognostic Roles of m6A-related Genes in Multiple Myeloma: YTHDF2 as the independent prognostic factor

Emerging Roles of N6-Methyladenosine Demethylases and Its Interaction with Environmental Toxicants in Digestive System Cancers

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