This review systematically synthesizes current knowledge regarding the multifaceted roles of YTHDC2 in disease progression, prognosis, and therapy, offering a comprehensive framework to guide future investigations.
Abstract
As a key N6-methyladenosine (m6A)-binding protein, YT521-B Homology (YTH) Domain-Containing Protein 2 (YTHDC2) plays a central role in the epitranscriptomic regulatory network. This protein specifically recognizes and binds to m6A modification sites on RNA molecules through its highly conserved YTH domain. This recognition exhibits high selectivity and affinity, thereby enabling precise control over the fate of target RNAs. At the molecular level, YTHDC2 is widely involved in various stages of the RNA life cycle, including core biological processes such as RNA splicing and processing, nuclear–cytoplasmic transport, translational efficiency regulation, and RNA decay. In recent years, accumulating evidence indicates that YTHDC2 participates in a variety of pathophysiological processes in an m6A-dependent manner. However, the robustness of evidence regarding YTHDC2 is heterogeneous across disease contexts. While certain pathologies are supported by rigorous mechanistic validation, others rely primarily on expression correlations or bioinformatic analyses. This review systematically synthesizes current knowledge regarding the multifaceted roles of YTHDC2 in disease progression, prognosis, and therapy, offering a comprehensive framework to guide future investigations.
The molecular mechanisms by which m6A regulates both coding and noncoding RNAs in HCC are summarized, the functional roles of key m6A regulators in hepatocarcinogenesis are highlighted, and the therapeutic potential of targeting the m6A machinery in HCC is discussed.
Xinning Luo, Cuiying Qin, Yi Feng et al.· Discover Oncology· 0 citations
N6-methyladenosine (m6A) is a prevalent epitranscriptional modification in RNA that is crucial for RNA metabolism and biogenesis. Accumulating evidence reveals a complex interplay between m6A and protein post-translational modifications (PTMs)-covalent additions of chemical groups or structural alterations to nascent proteins during or after biosynthesis. This crosstalk involves in disease development and drug response by altering protein properties and functions. Nevertheless, comprehensive discussion about the roles and mechanisms of m6A and PTMs crosstalk is limited. Here, we present an up-to-date review of this emerging and complex interplay in disease and therapeutic response. We first summarize the crosstalk between m6A and PTMs such as ubiquitination, lactylation, acetylation, phosphorylation, and methylation, organizing our discussion around the three major regulatory factors m6A writers, erasers, and readers. Next, we explore the mechanism of m6A-PTMs crosstalk involved in the pathogenesis and development of diseases, including various cancers, metabolic disorders, and inflammatory diseases. Moreover, we discuss the role of m6A-PTMs crosstalk in drug response, focusing on chemotherapy drugs. In summary, this review provides a framework for understanding the regulatory networks of m6A-PTMs crosstalk in disease pathogenesis, development, and therapeutic response, highlighting potential treatment strategies based on this interplay and suggesting future research directions.
Xinyi Li, Li-Ting Yang, Xian-Min Zhou et al.· Biochimica et Biophysica Act...· 0 citations
This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
Advances provide the first chemical foothold for therapeutic modulation of m7G pathways and underscore METTL1 as a promising yet complex target requiring careful biological stratification.
Emanuele Fabbrizi, Gebremedhin S. Hailu, Andrea Mancini et al.· Journal of Medicinal Chemist...· 0 citations
BACKGROUND
Osteosarcoma (OS) represents a common primary malignant bone tumor associated with unfavorable clinical outcomes. Growing evidence underscores the crucial involvement of N6-methyladenosine (m6A) modifications in tumor development, but the specific mechanisms underlying the m6A regulatory network in OS remain to be elucidated.
METHODS
Potential key target genes in OS were identified through bioinformatic analyses, followed by the characterization of m6A-related regulatory proteins, specifically, writer and reader proteins, which showed significant associations with these targets. To elucidate the mechanistic role of m6A methylation in regulating UHRF1 expression, a series of in vitro assays were conducted. These included RNA pull-down, MeRIP-PCR, dot blot, dual-luciferase reporter assays, and RNA stability assays, which collectively confirmed the interaction between m6A regulatory proteins and UHRF1 mRNA. For functional investigations, OS cell lines (U2OS, Saos2, and 143B) with gene silencing or overexpression were established, and the role of UHRF1 in cellular proliferation, migration, and invasion was assessed using CCK-8 assays, Transwell migration and invasion assays, flow cytometry, and wound healing assays. In addition, GSH/GSSG ratio, Fe2+ concentration, and ROS levels were measured using commercial assay kits to explore ferroptosis-related functional mechanisms. To validate the in vivo relevance of our findings, a xenograft mouse model was established. Finally, functional rescue experiments were performed to mechanistically confirm the critical role of the ZCCHC4-UHRF1-CDO1 regulatory axis in OS progression.
RESULTS
ZCCHC4, functioning as an m6A methyltransferase, enhances the stability of UHRF1 mRNA by catalyzing its m6A modification, thereby promoting increased expression of UHRF1. In parallel, IGF2BP3, an established m6A reader protein, specifically recognizes and binds to the m6A-modified sites on UHRF1 mRNA, further stabilizing the transcript and modulating its downstream biological functions. METTL3/METTL14 knockdown experiments ruled out the contribution of classical m6A methyltransferases, confirming that ZCCHC4 is the primary methyltransferase for UHRF1. Dual-luciferase assays and bisulfite sequencing revealed that UHRF1 suppresses CDO1 transcription by inducing high methylation of its promoter, thereby reducing ROS/Fe2+ levels and increasing GSH, which in turn blocks ferroptosis. In U2OS, Saos2, and 143B cells, silencing UHRF1 or ZCCHC4 inhibited proliferation, migration, and invasion while activating ferroptosis. Overexpression of UHRF1 had the opposite effect. In vivo models confirmed that UHRF1 silencing inhibited tumor growth. Furthermore, UHRF1 overexpression partially reversed the phenotypes induced by ZCCHC4 knockdown.
CONCLUSION
In summary, this study reveals for the first time the complete molecular mechanism by which ZCCHC4-mediated UHRF1 m6A methylation promotes OS progression through epigenetic suppression of CDO1 transcription and inhibition of ferroptosis. This regulatory axis (ZCCHC4-IGF2BP3-UHRF1-CDO1-ferroptosis) provides multiple therapeutic targets for OS and lays a solid foundation for the future development of anticancer strategies based on the regulation of ferroptosis, while also offering a promising pathway for clinical translation.
Kai Song, Ju Liu, Bowen Han et al.· Bone· 0 citations
It is argued that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.
A. Mukherjee, Ankit Kumar Bharti, D. Mathew et al.· Functional & Integrative Gen...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
