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Roles and mechanisms of the m6A reader YTHDC1 in biological processes and diseases

CELL DEATH DISCOVERY (2022)

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Article Cell Biology

m6A reader YTHDC1 modulates autophagy by targeting SQSTM1 in diabetic skin

Diefei Liang et al.

Summary: The dysregulation of autophagy, as well as the downregulation of SQSTM1 and YTHDC1, may contribute to delayed wound healing in diabetic skin. These findings suggest a previously unrecognized role for YTHDC1 in modulating autophagy through regulating SQSTM1 stability, highlighting a potential therapeutic target for improving wound healing in diabetes.

AUTOPHAGY (2022)

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Article Oncology

Cancer Statistics, 2021

Rebecca L. Siegel et al.

Summary: Every year, the American Cancer Society projects the numbers of new cancer cases and deaths in the United States, with the latest data showing a significant decline in lung cancer mortality, while prostate cancer mortality has plateaued and breast and colorectal cancer mortality have slowed. Improvements in treatment have accelerated progress against lung cancer, leading to a record drop in overall cancer mortality.

CA-A CANCER JOURNAL FOR CLINICIANS (2021)

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Article Biochemistry & Molecular Biology

N6-methyladenosine modification of circular RNA circ-ARL3 facilitates Hepatitis B virus-associated hepatocellular carcinoma via sponging miR-1305

Xi Rao et al.

Summary: The study identified a HBV-related circRNA, circ-ARL3, and demonstrated that silencing this circRNA inhibited the proliferation and invasion of HBV+ HCC cells, and was correlated with malignant clinical features and poor prognosis. Mechanistically, HBx protein upregulated METTL3 expression to increase m(6)A modification of circ-ARL3, promoting HBV+ HCC progression.

IUBMB LIFE (2021)

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Article Cell Biology

Depletion of m6A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of Titin

Siyun Gao et al.

Summary: This study demonstrates that deficiency of YTHDC1 contributes to dilated cardiomyopathy in mice, leading to abnormalities in cardiac contractile function and sarcomere arrangement. It highlights the crucial role of YTHDC1 in regulating normal cardiac biofunction and provides a potential target for DCM treatment.

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (2021)

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Article Oncology

Genetic variants in m6A modification core genes are associated with glioma risk in Chinese children

Jing He et al.

Summary: The study investigated the relationship between 24 functional single-nucleotide polymorphisms (SNPs) in eight m(6)A modification core genes and glioma risk, revealing several variants that were significantly associated with increased or decreased risk of glioma. The findings suggest that variants in m(6)A modification core genes play a role in pediatric glioma etiology, with some variants showing stronger associations in certain subgroups.

MOLECULAR THERAPY-ONCOLYTICS (2021)

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Article Oncology

The construction and validation of an RNA binding protein-related prognostic model for bladder cancer

Fengxia Chen et al.

Summary: This study established a prognostic model based on prognosis-related RBPs to predict the survival of BLCA patients. Eight independent prognosis-associated RBPs were identified to construct a risk score model, showing lower overall survival in high-risk subgroup and moderate predictive discrimination of the prognostic model. The nomogram established in this study showed favorable predictive value for the prognosis of BLCA.

BMC CANCER (2021)

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Article Multidisciplinary Sciences

METTL3 regulates heterochromatin in mouse embryonic stem cells

Wenqi Xu et al.

Summary: METTL3 regulates mouse embryonic stem-cell heterochromatin, critical for silencing retroviral elements and mammalian development. Through m(6)A methylation, METTL3 modulates integrity of IAP heterochromatin.

NATURE (2021)

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Article Multidisciplinary Sciences

The RNA m6A reader YTHDC1 silences retrotransposons and guards ES cell identity

Jiadong Liu et al.

Summary: The study reveals that the m(6)A RNA modification and YTHDC1 play essential roles in regulating retrotransposons and cellular reprogramming during early mouse embryonic development.

NATURE (2021)

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Article Genetics & Heredity

Effect of N6-Methyladenosine Regulators on Progression and Prognosis of Triple-Negative Breast Cancer

Shanshan Wang et al.

Summary: The study revealed that m^6A methylation regulators were significantly dysregulated in TNBC tissues, and could serve as a novel prognostic signature for predicting the survival of TNBC patients.

FRONTIERS IN GENETICS (2021)

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Article Cell Biology

m6A Regulators Is Differently Expressed and Correlated With Immune Response of Esophageal Cancer

Huaying Zhao et al.

Summary: This study revealed that aberrations in m6A regulators are closely associated with prognosis in esophageal cancer, with some regulators significantly correlated to disease severity and poor outcomes. The levels of m6A regulators are also related to the expression of immune regulators and immune infiltration levels in EC, suggesting their involvement in tumor progression through RNA binding and cell proliferation regulation.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Review Cell Biology

Emerging Roles of N6-Methyladenosine Modification in Neurodevelopment and Neurodegeneration

Liqi Shu et al.

Summary: N6-methyladenosine is the most abundant modification in mRNAs, deposited and erased by writers and erasers, and recognized by m(6)A-binding proteins. It plays essential roles in neurogenesis and neuronal development, with dysregulation potentially contributing to neurological disorders. This review summarizes the roles of m(6)A machinery in gene expression regulation and its function in neurodevelopment and neurodegeneration, discussing future perspectives for studying m(6)A methylation.

CELLS (2021)

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Article Virology

The RNA Binding Proteins YTHDC1 and FMRP Regulate the Nuclear Export of N6-Methyladenosine-Modified Hepatitis B Virus Transcripts and Affect the Viral Life Cycle

Geon-Woo Kim et al.

Summary: YTHDC1 and FMRP play significant roles in the HBV life cycle by facilitating the nuclear export of m(6)A-modified HBV transcripts, affecting RNA stability, translation, and ultimately the viral replication process.

JOURNAL OF VIROLOGY (2021)

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Article Biochemistry & Molecular Biology

N-6-Methyladenosine (m(6)A) readers are dysregulated in renal cell carcinoma

Felix von Hagen et al.

Summary: In clear cell renal carcinoma, the expression of m(6)A readers is significantly downregulated, with five out of six readers showing dysregulated protein levels. Lower expression levels of some m(6)A readers are correlated with advanced stage and grade of the tumor, as well as associated with shorter survival times.

MOLECULAR CARCINOGENESIS (2021)

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Article Cell Biology

Nuclear m6A reader YTHDC1 regulates the scaffold function of LINE1 RNA in mouse ESCs and early embryos

Chuan Chen et al.

Summary: The study reveals that YTHDC1 plays crucial roles in the self-renewal and differentiation of mouse embryonic stem cells, depending on its m(6)A binding ability. YTHDC1 recognizes m(6)A on LINE1 RNAs in the nucleus, regulating chromatin recruitment and transcriptional activities.

PROTEIN & CELL (2021)

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Article Cell Biology

Comprehensive Analysis of the Prognostic Role and Mutational Characteristics of m6A-Related Genes in Lung Squamous Cell Carcinoma

Chang Gu et al.

Summary: This study explored the prognostic role and mutational characteristics of m6A-related genes in LUSC, identifying three potential independent prognostic m6A-related genes (WTAP, YTHDC1, and YTHDF1) for OS in LUSC patients. The study used LUSC gene expression data and mutational data from The Cancer Genome Atlas database, identifying differentially expressed genes and exploring gene mutations in LUSC patients, investigating the correlations among m6A-related genes, and developing a nomogram model. The study also found significant co-occurrence frequencies among certain m6A-related genes and identified prognostic factors for OS in LUSC patients through multivariate Cox analysis.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2021)

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Article Cell Biology

Immune infiltration-related N6-methyladenosine RNA methylation regulators influence the malignancy and prognosis of endometrial cancer

Jian Ma et al.

Summary: This study revealed the significance of m6A RNA methylation regulator proteins in endometrial cancer progression, with ZC3H13, YTHDC1, and METTL14 identified as potential diagnostic and prognostic markers. The findings also indicated a correlation between immune cell infiltration and the expression of these proteins, and demonstrated that knockdown of ZC3H13 or YTHDC1 promoted proliferation and invasion of endometrial cancer cells. Additionally, a regulatory network involving the m6A regulators was constructed, and potential therapeutic compounds interacting with METTL14 and YTHDC1 were predicted through virtual screening.

AGING-US (2021)

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Article Hematology

A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication

Yue Sheng et al.

Summary: YTHDC1 functions as a nuclear m(6)A reader in RNA metabolism regulation, with its overexpression shown in AML. Genetic deletion of Ythdc1 blocks AML development and maintenance, as well as LSCs self-renewal. YTHDC1 also plays a role in normal hematopoiesis and HSPC maintenance, with haploinsufficiency reducing LSCs self-renewal in vivo.

BLOOD (2021)

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Article Oncology

N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

Yuanming Cheng et al.

Summary: The study revealed the crucial role of m(6)A in myeloid leukemia, where it maintains cell survival and the undifferentiated state necessary for leukemia maintenance through the formation of nuclear YTHDC1-m(6)A condensates.

CANCER CELL (2021)

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Article Biochemistry & Molecular Biology

YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect

Yichao Hou et al.

Summary: The study demonstrates that miR-30d is downregulated in PDAC tissues, exerting tumor-suppressive effects by inhibiting tumor growth and metastasis, and reducing the Warburg effect through suppression of aerobic glycolysis. The m(6)A reader YTHDC1 facilitates the biogenesis of miR-30d by regulating mRNA stability. MiR-30d inhibits aerobic glycolysis by directly targeting the transcription factor RUNX1 and suppressing SLC2A1 and HK1 expression in PDAC.

CELL DEATH AND DIFFERENTIATION (2021)

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Article Biotechnology & Applied Microbiology

Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Kuan Hu et al.

Summary: Expression profiles of the YTH family were dysregulated in LUAD, with lower expression of YTHDC1 and YTHDC2 and higher expression of YTHDF1, YTHDF2, and YTHDF3. Lower expression of YTHDC2, YTHDF1, and YTHDF2 was associated with better overall survival in LUAD patients, suggesting potential therapeutic targets.

DISEASE MARKERS (2021)

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Article Cell Biology

Epitranscriptomic addition of m6A regulates HIV-1 RNA stability and alternative splicing

Kevin Tsai et al.

Summary: Previous studies have shown that the addition of m(6)A to viral transcripts can enhance replication and pathogenicity of various viruses, including HIV-1. The mechanisms underlying this effect are largely mediated by m(6)A binding proteins, with YTHDC1 and YTHDF2 playing key roles in regulating HIV-1 gene expression. Unexpectedly, YTHDF2 binding to m(6)A sites on HIV-1 transcripts leads to increased stability, contrasting its destabilizing effect on cellular mRNAs containing m(6)A residues.

GENES & DEVELOPMENT (2021)

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Article Biochemistry & Molecular Biology

N6-methyladenosine-modified circIGF2BP3 inhibits CD8+ T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer

Zhenchuan Liu et al.

Summary: In this study, it was found that circIGF2BP3 contributes to immune escape in NSCLC by upregulating PKP3 expression and stabilizing OTUB1 mRNA to increase PD-L1 abundance. The impact on the CD8(+) T cell response was observed, shedding light on a novel mechanism of PD-L1 regulation in NSCLC and providing insight on enhancing the efficacy of anti-PD-1 treatment.

MOLECULAR CANCER (2021)

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Article Biochemistry & Molecular Biology

Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation

Joo-Hyung Lee et al.

Summary: The study reveals the heavy but selective deposition of m6A on nascent RNAs produced by transcription regulatory elements, and shows that m6A-eRNAs mark highly active enhancers by recruiting YTHDC1 and promoting condensate formation. This mechanism plays broad roles in enhancer activation and gene transcriptional control.

MOLECULAR CELL (2021)

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Article Cell Biology

EMP3 negatively modulates breast cancer cell DNA replication, DNA damage repair, and stem-like properties

Kailing Zhou et al.

Summary: EMP3 acts as a potential tumor suppressor in breast cancer by inhibiting cell cycle progression, DNA repair, and stem-like properties, leading to enhanced sensitivity of breast cancer cells to DNA-damaging agents.

CELL DEATH & DISEASE (2021)

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Article Medicine, Research & Experimental

m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression

Dawei Rong et al.

Summary: m6A-modified circRNA circHPS5 plays a crucial role in HCC development by regulating phenotype and signaling pathways, impacting the growth and metastasis of HCC cells and affecting patient prognosis.

MOLECULAR THERAPY-NUCLEIC ACIDS (2021)

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Article Genetics & Heredity

Characterization of Modification Patterns, Biological Function, Clinical Implication, and Immune Microenvironment Association of m6A Regulators in Pancreatic Cancer

Kun Fang et al.

Summary: The study identified genetic mutations and dysregulation in m(6)A regulators in pancreatic cancer, leading to different prognosis, immune cell infiltration, and biological functions. A m(6)A scoring system was developed to show that high m(6)A scores are associated with poor clinical outcomes and more frequent mutations. Additionally, the study found that the m(6)A scores may be useful in predicting the response to immunotherapy.

FRONTIERS IN GENETICS (2021)

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Article Cell Biology

m6A RNA methylation regulators contribute to malignant progression in rectal cancer

Jinfu Zhuang et al.

JOURNAL OF CELLULAR PHYSIOLOGY (2020)

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Article Biochemistry & Molecular Biology

The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

Tao Liu et al.

NUCLEIC ACIDS RESEARCH (2020)

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Article Multidisciplinary Sciences

N6-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription

Jun Liu et al.

SCIENCE (2020)

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Modulation of circRNA Metabolism by m6A Modification

Gaia Di Timoteo et al.

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The potential role of RNA N6-methyladenosine in Cancer progression

Tianyi Wang et al.

MOLECULAR CANCER (2020)

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N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2

Yuan Li et al.

NATURE GENETICS (2020)

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Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop in blood malignancies

Zhen-Hua Chen et al.

CELL DEATH & DISEASE (2020)

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m6A RNA Methylation Regulators Participate in the Malignant Progression and Have Clinical Prognostic Value in Lung Adenocarcinoma

Fangwei Li et al.

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YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis

Guoqiang Chang et al.

CANCER CELL (2020)

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Article Cell Biology

YTHDC1 mitigates ischemic stroke by promoting Akt phosphorylation through destabilizing PTEN mRNA

Zhaolong Zhang et al.

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YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer

Jiangfeng Li et al.

MOLECULAR CANCER (2020)

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Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma

Yufeng Shi et al.

NATURE (2019)

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N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma

Fuxi Li et al.

CANCER RESEARCH (2019)

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The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing

Hayley J. Luxton et al.

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N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis

Ri-Xin Chen et al.

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Gene signatures and prognostic values of m6A regulators in clear cell renal cell carcinoma - a retrospective study using TCGA dataoase

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