YTHDF1 promotes mRNA degradation via YTHDF1‐AGO2 interaction and phase separation

Li, Jiong; Chen, Ke; Dong, Xin; Xu, Yating; Sun, Qi; Wang, Honghong; Chen, Zhe; Liu, Cong; Liu, Rong; Yang, Zhe; Mei, Xiangfei; Zhang, Rongyu; Chang, Liuping; Tian, Zhenjun; Chen, Jianjun; Liang, Kaiwei; He, Chunjiang; Luo, Mengcheng

doi:10.1111/cpr.13157

Cited by 58 publications

(41 citation statements)

References 45 publications

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“…As is well known, the complex mechanisms of m6A regulation coordinated by methyltransferases (writers), demethylases (erasers), and reader proteins [ 24 ]. At present, several m6A readers (YTHDF1, YTHDF2, YTHDF3, and YTHDC1) have been confirmed to be involved in RNA degradation [ 22 , 25 – 29 ]. Thus, RNA pull-down assay was performed and these protein were detected by western blot.…”

Section: Resultsmentioning

confidence: 99%

N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis

et al. 2022

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Circular RNAs (circRNAs) are a recently discovered kind of regulatory RNAs that have emerged as critical biomarkers of various types of cancers. Metabolic reprogramming has gradually been identified as a distinct hallmark of cancer cells. The pentose phosphate pathway (PPP) plays an indispensable role in satisfying the bioenergetic and biosynthetic demands of cancer cells. However, little is known about the role of circRNAs and PPP in colorectal cancer (CRC). The novel circ_0003215 was identified at low levels in CRC and was negatively correlated with larger tumor size, higher TNM stage, and lymph node metastasis. The decreased level of circ_0003215 was resulted from the RNA degradation by m6A writer protein YTHDF2. A series of functional assays demonstrated that circ_0003215 inhibited cell proliferation, migration, invasion, and CRC tumor metastasis in vivo and in vitro. Moreover, circ_0003215 regulated the expression of DLG4 via sponging miR-663b, thereby inducing the metabolic reprogramming in CRC. Mechanismly, DLG4 inhibited the PPP through the K48-linked ubiquitination of glucose-6-phosphate dehydrogenase (G6PD). Taken together, we have identified m6A-modified circ_0003215 as a novel regulator of metabolic glucose reprogramming that inhibited the PPP and the malignant phenotype of CRC via the miR-663b/DLG4/G6PD axis.

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Section: Resultsmentioning

confidence: 99%

N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis

et al. 2022

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“…For shRNA knockdown experiments, independent shRNAs targeting a different region of MCM4 RNA were constructed using a pLKO.1 vector (Addgene), and the oligo sequences were provided in follow. Lenti-viruses were generated according to the manufacture protocol as previously documented ( 23 ) and indicated cells were infected by viruses twice with 48 h and 72 h viral supernatants containing 4 μg/mL polybrene, and stable cell lines were established by appropriate puromycin selection. The two independent MCM4 targeting sequences are: shRNA#1, 5’-GGGTGGAGATGGACCGCGGCC-3’; shRNA#2, 5’-GCCTTGATGAAGAAGCAGAAC-3’.…”

Section: Methodsmentioning

confidence: 99%

MCM4 is a novel prognostic biomarker and promotes cancer cell growth in glioma

et al. 2022

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BackgroundGliomas account for 75% of all primary malignant brain tumors in adults and result in high mortality. Accumulated evidence has declared the minichromosome maintenance protein complex (MCM) gene family plays a critical role in modulating the cell cycle and DNA replication stress. However, the biological function and clinic characterization of nine MCM members in low-grade glioma are not yet clarified.MethodsIn this study, we utilized diverse public databases, including The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt, Human Protein Atlas (HPA), Linkedomics, cbioportal, Tumor and Immune System Interaction Database (TISIDB), single-sample GSEA (ssGSEA), Tumor Immune Estimation Resource (TIMER), Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal databases to explore the mRNA and protein expression profiles, gene mutation, clinical features, diagnosis, prognosis, signaling pathway, tumor mutational burden (TMB), immune subtype, immune cell infiltration, immune modulator and drug sensitivity of nine MCMs. Afterward, qRT-PCR was utilized to detect the expression of the MCM family in glioblastoma multiforme (GBM) cell lines. The one-, three-, or five-year survival rate was predicted by utilizing a nomogram established by cox proportional hazard regression.ResultsIn this study, we found that nine MCMs were consistently up-regulated in glioma tissues and glioma cell lines. Elevated nine MCMs expressions were significantly correlated with a higher tumor stage, isocitrate dehydrogenase (IDH) mutates, 1p/19q codeletion, histological type, and primary therapy outcome. Survival analyses showed that higher expression of MCM2-MCM8 (minichromosome maintenance protein2-8) and MCM10 (minichromosome maintenance protein 10) were linked with poor overall survival (OS) and progression-free survival (PFS) in glioma patients. On the other hand, up-regulated MCM2-MCM8 and MCM10 were significantly associated with shorter disease-specific survival (DSS) in glioma patients. Univariate and multivariate analyses revealed that MCM2 (minichromosome maintenance protein2), MCM4 (minichromosome maintenance protein 4), MCM6 (minichromosome maintenance protein 6), MCM7 (minichromosome maintenance protein 7) expression and tumor grade, 1p/19q codeletion, age, and primary therapy outcome were independent factors correlated with the clinical outcome of glioma patients. More importantly, a prognostic MCMs model constructed using the above five prognostic genes could predict the overall survival of glioma patients with medium-to-high accuracy. Furthermore, functional enrichment analysis indicated that MCMs principal participated in regulating cell cycle and DNA replication. DNA copy number variation (CNV) and DNA methylation significantly affect the expression of MCMs. Finally, we uncover that MCMs expression is highly correlated with immune cell infiltration, immune modulator, TMB, and drug sensitivity.ConclusionsIn summary, this finding confirmed that MCM4 is a potential target of precision therapy for patients with glioma.

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“…The formation of BRD4 coactivator LLPS condensates can be promoted by YTHDC1/m6A-eRNA phase separation condensate co-mixes 99 . In addition, mRNA degradation can be promoted by YTHDF1 phase separation and the interaction of YTHDF1-AGO2 100 . These studies showed that the composition of intracellular LLPS transcriptome can be regulated by the distribution and number of m6A sites in mRNA, which indicates that phase separation can control the cellular characteristics of m6A modified mRNA.…”

Section: The Regulation Of Llps Condensatesmentioning

confidence: 99%

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

Qiu¹,

Tan²,

Xia³

et al. 2022

Int. J. Biol. Sci.

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Cancer is a public health problem of great concern, and it is also one of the main causes of death in the world. Cancer is a disease characterized by dysregulation of diverse cellular processes, including avoiding growth inhibitory factors, avoiding immune damage and promoting metastasis, etc. However, the precise mechanism of tumorigenesis and tumor progression still needs to be further elucidated. Formations of liquid-liquid phase separation (LLPS) condensates are a common strategy for cells to achieve diverse functions, such as chromatin organization, signal transduction, DNA repair and transcriptional regulation, etc. The biomolecular aggregates formed by LLPS are mainly driven by multivalent weak interactions mediated by intrinsic disordered regions (IDRs) in proteins. In recent years, aberrant phase separations and transition have been reported to be related to the process of various diseases, such as neurodegenerative diseases and cancer. Herein, we discussed recent findings that phase separation regulates tumor-related signaling pathways and thus contributes to tumor progression. We also reviewed some tumor virus-associated proteins to regulate the development of virus-associated tumors via phase separation. Finally, we discussed some possible strategies for treating tumors by targeting phase separation.

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YTHDF1 promotes mRNA degradation via YTHDF1‐AGO2 interaction and phase separation

Cited by 58 publications

References 45 publications

N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis

N6-methyladenosine modification of circ_0003215 suppresses the pentose phosphate pathway and malignancy of colorectal cancer through the miR-663b/DLG4/G6PD axis

MCM4 is a novel prognostic biomarker and promotes cancer cell growth in glioma

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

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