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PLEK2 functions as a co-factor of YTHDF2 to enhance TYMS mRNA stability in colorectal cancer

ABSTRACT: PLEK2 functions as a co-factor of YTHDF2 to enhance TYMS mRNA stability in colorectal cancer

PROVIDER: PRJNA1058977 | ENA |

REPOSITORIES: ENA

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PLEK2 functions as a co-factor of YTHDF2 to enhance TYMS mRNA stability in colorectal cancer

Project description:High expression of nucleotide synthetic enzyme thymidylate synthase (TYMS) is responsible for the resistance to fluorouracil (FU) treatment and worse survival in colorectal cancer. Herein, we revealed that Pleckstrin-2 (PLEK2), highly expressed in CRC, enhanced TYMS mRNA stability via its interaction with YTHDF2 in a m6A-dependent manner. Silencing of PLEK2 led to the downregulation of TYMS, and consequent inhibition of CRC cell proliferation via the cellular senescence. Additionally, PLEK2 is also required for CRC cell migration, invasion and stemness-like properties. PLEK2 inhibition is sufficient to ameliorate the progression of CRC. Moreover, loss of PLEK2 inhibited AOM/DSS-induced colonic tumorigenesis in vivo. Together, our study identified PLEK2 as a key regulator for the progress of CRC via the regulation of TYMS expression, and demonstrated that PLEK2 is a novel therapeutic target for CRC.

2025-07-23 | GSE252234 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

Project description:As the third most common cause of cancer-related mortality, hepatocellular carcinoma (HCC) is a global health concern. Despite its prevalence, treatment options are limited, underscoring the need to identify potential therapeutic targets and strategies. Here, we identified amplification of CRTC2, situated in the 1q21.3 region, due to copy number alterations in HCC. In a cohort of patients with HCC, CRTC2 protein levels were frequently elevated and correlated with poor prognosis. Genetic depletion of CRTC2 significantly impeded the onset and progression of HCC in mouse models. CRTC2 formed cytoplasmic condensates that recruited the m6A reader YTHDF2. Furthermore, CRTC2 promoted the translocation of m6A-modified mRNAs from decay sites to polyribosomes by interacting with PABP1. The activities of CRTC2 counteracted YTHDF2-mediated mRNA degradation to enhance the translational efficiency of specific mRNAs, including those encoding LRP5 and c-Jun. Targeting CRTC2 in hepatocytes using AAV8.sgCRTC2 elicited substantial therapeutic benefits in HCC mouse model and significantly enhanced the sensitivity to lenvatinib. Together, this research elucidates the pivotal role and underlying molecular mechanisms of CRTC2 in hepatocarcinogenesis and lenvatinib-resistance, highlighting its potential clinical and therapeutic applications.

2025-02-08 | GSE264246 | GEO

Cell cycle-dependent YTHDF2 promotes mitotic entry by repressing WEE1

Project description:The m6A modification regulates mRNA stability and translation. Here we show that transcriptomic m6A modification is dynamic and the m6A reader protein YTHDF2 promotes mRNA decay during the cell cycle. Depletion of YTHDF2 leads to the delay of mitotic entry due to overaccumulation of WEE1, a negative regulator of CDK1. We demonstrate that WEE1 transcripts contain m6A modification, which promotes their decay through the m6A reader YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on CDK1 activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified CUL1, CUL4A, DDB1, and SKP2 as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m6A modification, which in turn regulates the cell cycle.

2020-01-01 | GSE134700 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (RNA-seq)

2025-02-10 | GSE289166 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (m6A-seq)

2025-02-08 | GSE264244 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (CRTC2-RIPseq)

2025-02-08 | GSE264239 | GEO

CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

Project description:CRTC2 Forms Co-condensates with YTHDF2 that Enhance Translational Efficiency of m6A-Modified mRNAs to Drive Hepatocarcinogenesis and Lenvatinib Resistance (YTHDF2-RIPseq)

| PRJNA1101539 | ENA

Microarray profiling of YTHDF2 deficient mouse oocytes

Project description:To study the role of the protein YTHDF2 during female gametogenesis, its gene was conditionally deleted in oocytes. Total RNA samples from YTHDF2 deficient GV and MII oocytes (and control oocytes) were subjected to array profiling.

2018-02-12 | E-MTAB-5576 | biostudies-arrayexpress

MeRIP, RIP and RNA Sequencing of the H1299 stable cell lines which the endogenous YTHDF2 was silenced by a short hairpin RNA targeting YTHDF2 3’UTR (shYTHDF2) and then re-expressed Flag-tagged YTHDF2-WT orYTHDF2-K571R

Project description:SUMOylation affects many aspects of target proteins such as activity, stability, localization and protein-protein interactions. We have found that SUMOylation of YTHDF2 increased its binding activity with m6A-RNAs by using different experimental approaches. To confiremd this conclusion,the analysis of RIP-seq, MeRIP-seq and RNA-seq in H1299-shYTHDF2 cells re-expressing YTHDF2-WT and YTHDF2-K571R was performed. MeRIP+RIP targets showed lower binding affinities in the mutant YTHDF2-K571R when compared with YTHDF2-WT. Compared to the control group, the binding capacities of YTHDF2 to RIP targets in treated group with either 2-D08 or GA were decreased, especially to MeRIP+RIP targets. Moreover, SUMOylated YTHDF2 promoted m6A-RNAs degradation. Combined analysis of RNA-seq, RIP-seq and MeRIP-seq showed that the mRNA levels were up-regulated in shYTHDF2 stable cells re-expressing YTHDF2-K571R compared with those in re-expressing YTHDF2-WT.

2021-01-26 | GSE164917 | GEO

YTHDF2 regulates self non-coding RNA metabolism to control TLR3 activation in Inflammation

Project description:To elucidate the roles of YTHDF2 in the UV response in Human Keratinocyte (HaCaT) cells, the YTHDF2 interactome was analyzed through immunoprecipitation using a YTHDF2-specific antibody. Control IgG served as a negative control in this study. The cells were treated with UVB at 20 mJ/cm², and one hour post-treatment, alterations in the binding partners interacting with YTHDF2, along with their post-translational modifications, were analyzed using proteomics.

2025-09-10 | PXD059422 | Pride

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