Ticket to divide: m6A reader YTHDC1 drives acute myeloid leukemia proliferation.
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ABSTRACT:
SUBMITTER: Volk A
PROVIDER: S-EPMC8718629 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Muscle stem cells are required for the homeostasis and regeneration of mammalian skeletal muscles. It has been reported that RNA N6-methyladenosine (m6A) modifications play a pivotal role in muscle development and regeneration. Nevertheless, we know little about which m6A reader regulates mammalian muscle stem cells. Here, we discovered that the m6A reader Ythdc1 is indispensable for mouse skeletal muscle regeneration and proliferation of muscle stem cells. In the absence of Ythdc1, Muscle stem cells in adult mice are unable to exit from quiescence. Mechanistically, Ythdc1 binds to m6A-modified Pi4k2a and Pi4kb mRNAs to regulate their alternative splicing and thus PI4K-Akt-mTOR signalling. Ythdc1-null muscle stem cells show a deficiency in phosphatidylinositol (PI) 3,4,5-trisphosphate, phospho-Akt and phospho-S6, which correlates with a failure in exit from quiescence. Our findings connect dynamic RNA methylation to the regulation of PI4K-Akt-mTOR signalling during stem cell proliferation and adult tissue regeneration.
| S-EPMC10392063 | biostudies-literature
Project description:N6-methyladenosine (m6A) is the most abundant posttranscriptional modification of mRNA in eukaryotes. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), a subtype of leukemia associated with poor prognosis and high genetic risk. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 dramatically suppresses the apoptosis, reduces the proliferation, and impairs the leukemic capacity of AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-modified RNA. Thus, we provided compelling evidence demonstrating that the m6A reader IGF2BP3 contributes to tumorigenesis and poor prognosis in AML and can serve as a target for the development of cancer therapeutics.
| S-EPMC8894383 | biostudies-literature
Project description:BackgroundCholangiocarcinoma (CCA) is a serious malignancy originating from the bile ducts and the second most common primary liver cancer. Long non-coding RNA (lncRNA) is a functional lncRNA that plays an important role in human cancers. However, the role and underlying mechanisms of CTBP1-AS2 in CCA remain unknown.PurposeIn this study, we investigated the functional role and mechanism of long-stranded non-coding RNA (lncRNA) C-terminal binding protein 1 antisense RNA 2 (CTBP1-AS2) in CCA progression.ResultIn the present study, the bioinformatics analysis revealed that YTHDC1 and CTBP1-AS2 were significantly upregulated, and it was confirmed in cholangiocarcinoma tissues from CCA patients. Meanwhile, we demonstrated that knockdown of YTHDC1 or lncRNA CTBP1-AS2 inhibited CCA cell proliferation, migration and invasion, blocked the cell cycle in G2/M phase and promoted apoptosis of CCA cells. In addition, lncRNA CTBP1-AS2-mediated N6-methyladenosine (m6A) methylation levels were significantly elevated in cholangiocarcinoma tissues, whereas knockdown of YTHDC1 resulted in a significant down-regulation of m6A methylation levels by lncRNA CTBP1-AS2.ConclusionOur results suggest that YTHDC1 affects cholangiocarcinoma progression by modifying the lncRNA CTBP1-AS2 m6A, and CTBP1-AS2 may be a promising therapeutic target for CCA.
| S-EPMC10559219 | biostudies-literature
Project description:Skeletal muscle stem cells (also known as satellite cells [SCs]) are essential for muscle regeneration and the regenerative activities of SCs are intrinsically governed by gene regulatory mechanisms, but the post-transcriptional regulation in SCs remains largely unknown. N(6)-methyladenosine (m6A) modification of RNAs is the most pervasive and highly conserved RNA modification in eukaryotic cells; it exerts powerful impact on almost all aspects of mRNA processing that is mainly endowed by its binding with m6A reader proteins. In this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, an m6A reader in mouse SCs. Our results demonstrate that YTHDC1 is an essential regulator of SC activation and proliferation upon acute injury-induced muscle regeneration. The induction of YTHDC1 is indispensable for SC activation and proliferation; thus, inducible YTHDC1 depletion almost abolishes SC regenerative capacity. Mechanistically, transcriptome-wide profiling using LACE-seq in both SCs and mouse C2C12 myoblasts identifies m6A-mediated binding targets of YTHDC1. Next, splicing analysis defines splicing mRNA targets of m6A-YTHDC1. Furthermore, nuclear export analysis also leads to the identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts;interestingly, some mRNAs can be regulated at both splicing and export levels. Lastly, we map YTHDC1 interacting protein partners in myoblasts and unveil a myriad of factors governing mRNA splicing, nuclear export, and transcription, among which hnRNPG appears to be a bona fide interacting partner of YTHDC1. Altogether, our findings uncover YTHDC1 as an essential factor controlling SC regenerative ability through multifaceted gene regulatory mechanisms in mouse myoblast cells.
| S-EPMC10089659 | biostudies-literature
Project description:The N6-methyladenosine (m6A) modification is the most prevalent internal RNA modification in eukaryotes. The majority of m6A sites are found in the last exon and 3' UTRs. Here we show that the nuclear m6A reader YTHDC1 is essential for embryo viability and germline development in mouse. Specifically, YTHDC1 is required for spermatogonial development in males and for oocyte growth and maturation in females; Ythdc1-deficient oocytes are blocked at the primary follicle stage. Strikingly, loss of YTHDC1 leads to extensive alternative polyadenylation in oocytes, altering 3' UTR length. Furthermore, YTHDC1 deficiency causes massive alternative splicing defects in oocytes. The majority of splicing defects in mutant oocytes are rescued by introducing wild-type, but not m6A-binding-deficient, YTHDC1. YTHDC1 is associated with the pre-mRNA 3' end processing factors CPSF6, SRSF3, and SRSF7. Thus, YTHDC1 plays a critical role in processing of pre-mRNA transcripts in the oocyte nucleus and may have similar non-redundant roles throughout fetal development.
| S-EPMC5991768 | biostudies-literature
Project description:N6-methyladenosine (m6A) and alternative polyadenylation (APA) are important regulators of gene expression in eukaryotes. Recently, it was found that m6A is closely related to APA. However, the molecular mechanism of this new APA regulation remains elusive. Here we show that YTHDC1, a nuclear m6A reader, can suppress proximal APA sites and produce longer 3' UTR transcripts by binding to their upstream m6A sites. YTHDC1 can directly interact with the 3' end processing factor FIP1L1 and interfere with its ability to recruit CPSF4. Binding to the m6A sites can promote liquid-liquid phase separation of YTHDC1 and FIP1L1, which may play an important role in their interaction and APA regulation. Collectively, YTHDC1 as an m6A "reader" links m6A modification with pre-mRNA 3' end processing, providing a new mechanism for APA regulation.
| S-SCDT-10_15252-EMBR_202254686 | biostudies-other
Project description:Background: N6-Methyladenosine (m6A) is considered to be the most prevalent and abundant internal modification observed in mRNA between viruses and mammals. As a reversible epigenetic modification, m6A controls gene expression in diverse physiological and pathological processes. Accumulating evidence in recent years reveals that aberrant expression of m6A reader proteins may have tumor-suppressing or carcinogenic functions. However, the biological role and mechanism of m6A reader YTH Domain Containing 1 (YTHDC1) in ovarian cancer progression remain inadequately understood. Methods: Quantitative RT-PCR, immunohistochemistry, Western blot, and bioinformatics analyses were undertaken for studying the YTHDC1 expression in ovarian cancer. In vitro and in vivo models were used to examine the role of YTHDC1. RNA sequencing, RNA immunoprecipitation sequencing, m6A-modified RNA immunoprecipitation, actinomycin-D assay, chromatin immunoprecipitation, and Western blot were used in the investigation the regulatory mechanisms among YTHDC1, Signal Transducer and Activator of Transcription 3 (STAT3), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Glucosidase II Alpha Subunit (GANAB). Results: Here, we found that YTHDC1 expression is decreased in ovarian cancer. Overexpression of YTHDC1 inhibited ovarian cancer development both in vivo and in vitro. Mechanistically, PIK3R1 was identified to be the direct target for YTHDC1. YTHDC1 enhanced PIK3R1 stability in an m6A-dependent manner, which subsequently inhibited GANAB expression in the N-glycan biosynthesis via the STAT3 signaling. Conclusions: Our findings unveil YTHDC1 as a tumor suppressor in the progression of ovarian cancer and as a potential prognostic biomarker that could serve as a target in ovarian cancer treatment.
| S-EPMC10535707 | biostudies-literature
Project description:YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.
| S-EPMC8718631 | biostudies-literature
Project description:Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.SignificanceCD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
| S-EPMC10472106 | biostudies-literature
Project description:Kinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of PTEN. While PTEN loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.
| S-EPMC6791388 | biostudies-literature