The roles and mechanisms of the m6A reader protein YTHDF1 in tumor biology and human diseases

Chen, Zuyao; Zhong, Xiaolin; Xia, Min; Zhong, Jue

doi:10.1016/j.omtn.2021.10.023

Cited by 64 publications

(52 citation statements)

References 85 publications

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“…Previous studies revealed that YTHDF1 regulates translation of different mRNAs under various physiological environments 39 . In this study, we found that YTHDF1 affecting genes enrich in several classic oncogenic pathways and inflammation pathways, including EGFR and TNF pathways.…”

Section: Discussionmentioning

confidence: 53%

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Huang

Zhu

Wang

et al. 2022

J of Gastro and Hepatol

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Background and Aim: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive disease with the underlying mechanisms poorly understood. YTHDF1, an N 6methyladenosine (m 6 A) reader protein, has important physiological functions in regulation of tumor development. However, the effect of YTHDF1 on ICC progression remains unknown yet. Methods: The expression level of YTHDF1 in human ICC tissue was examined in The Cancer Genome Atlas database and our cohort. The role of YTHDF1 was detected using two human ICC cell lines in vitro. An ICC tumorigenesis mouse model was established via hydrodynamic transfection of AKT/YAP plasmids. m 6 A sequencing, RNA immunoprecipitation sequencing, and RNA sequencing were carried out to explore the mechanism of YTHDF1 modulating ICC progression.Results: Here, we find that YTHDF1 is upregulated in ICC and associated with shorter survival of ICC patients. Depletion of YTHDF1 inhibits cell proliferation, migration, and invasion, while overexpression of wild-type YTHDF1, but not m 6 A reader domain mutant YTHDF1, significantly enhances tumor cell growth and aggressive abilities in vitro. Moreover, overexpression of YTHDF1 promotes the AKT/YAP transfection-induced orthotopic ICC tumorigenesis and progression in vivo. Mechanistically, we identify that YTHDF1 regulates the translation of epidermal growth factor receptor (EGFR) mRNA via binding m 6 A sites in the 30-UTR of EGFR transcript, thus leading to aberrant activities of downstream signal pathways that impact tumor progression. Conclusions: Our data uncover the oncogenic function and m 6 A reader-dependent mechanism of YTHDF1 in regulation of ICC progression. Restricting abnormal oncogenic mRNA translation by targeting YTHDF1 may be a novel and promising strategy for ICC treatment.

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Section: Discussionmentioning

confidence: 53%

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Huang

Zhu

Wang

et al. 2022

J of Gastro and Hepatol

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“…Although cisplatin therapy has achieved good prognosis and survival rates in patients with cancer, problems of drug resistance and considerable side effects remain ( Galluzzi et al, 2012 ). YTHDF1, an m6A “reader”, is an important regulator of tumour progression ( Chen et al, 2021c ). The expression of YTHDF1 is significantly upregulated in CRC, and its overexpression can reduce the sensitivity of colon cancer cells to cisplatin.…”

Section: Effects Of N6-methyladenosine On Drugs In Tumour Therapymentioning

confidence: 99%

Role of N6-Methyladenosine Methylation Regulators in the Drug Therapy of Digestive System Tumours

et al. 2022

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Digestive system tumours, including stomach, colon, esophagus, liver and pancreatic tumours, are serious diseases affecting human health. Although surgical treatment and postoperative chemoradiotherapy effectively improve patient survival, current diagnostic and therapeutic strategies for digestive system tumours lack sensitivity and specificity. Moreover, the tumour’s tolerance to drug therapy is enhanced owing to tumour cell heterogeneity. Thus, primary or acquired treatment resistance is currently the main hindrance to chemotherapy efficiency. N6-methyladenosine (m6A) has various biological functions in RNA modification. m6A modification, a key regulator of transcription expression, regulates RNA metabolism and biological processes through the interaction of m6A methyltransferase (“writers”) and demethylase (“erasers”) with the binding protein decoding m6A methylation (“readers”). Additionally, m6A modification regulates the occurrence and development of tumours and is a potential driving factor of tumour drug resistance. This review systematically summarises the regulatory mechanisms of m6A modification in the drug therapy of digestive system malignancies. Furthermore, it clarifies the related mechanisms and therapeutic prospects of m6A modification in the resistence of digestive system malignancies to drug therapy.

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“…N 6 -methyladenosine (m 6 A) modification is a dynamic and reversible process and is the most pervasive modification in human mRNA. M 6 A methylation plays an important role in a wide variety of biological and pathological processes including cancer development. m 6 A regulators can be divided into three types: writers, erasers, and readers.…”

Section: Introductionmentioning

confidence: 99%

“…M 6 A methylation plays an important role in a wide variety of biological and pathological processes including cancer development. m 6 A regulators can be divided into three types: writers, erasers, and readers. The differential m 6 A profile is an emerging hallmark of cancer.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

Chen

Cheung

Lau

et al. 2022

Cancers

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N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic cell mRNA, and this modification plays a key role in regulating mRNA translation, splicing, and stability. Emerging evidence implicates aberrant m6A as a crucial player in the occurrence and development of diseases, especially GI cancers. Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation. Here, we summarized the function, molecular mechanisms, and clinical implications of YTHDF1 in GI cancers. YTHDF1 is largely upregulated in multiple GI cancer and its high expression predicts poor patient survival. In vitro and in vivo experimental evidence largely supports the role of YTDHF1 in promoting cancer initiation, progression, and metastasis, which suggests the oncogenic function of YTHDF1 in GI cancers. Besides, YTHDF1 overexpression is associated with changes in the tumor microenvironment that are favorable to tumorigenesis. Mechanistically, YTHDF1 regulates the expression of target genes by promoting translation, thereby participating in cancer-related signaling pathways. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy. In summary, YTHDF1-mediated regulation of m6A modified mRNA is an actionable target and a prognostic factor for GI cancers.

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The roles and mechanisms of the m6A reader protein YTHDF1 in tumor biology and human diseases

Cited by 64 publications

References 85 publications

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

YTHDF1 promotes intrahepatic cholangiocarcinoma progression via regulating EGFR mRNA translation

Role of N6-Methyladenosine Methylation Regulators in the Drug Therapy of Digestive System Tumours

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

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