The molecular regulatory networks of CELF4 and its mechanisms across multisystem diseases are reviewed, the current status and limitations of clinical translation are discussed, and future research on diagnostic biomarkers and therapeutic strategies targeting this protein is guided.
Abstract
CELF4 (CUGBP Elav-like family member 4), encoded by the human chromosome 18q12.2 locus, is an RNA-binding protein that recognizes UG-rich sequences within the 3′untranslated region (3′UTR) of target mRNAs to regulate splicing, stability, and local translation at the post-transcriptional level. Under physiological conditions, CELF4 exerts translational repression during synaptic development in the central nervous system (CNS), maintains excitatory homeostasis, and sets peripheral sensory thresholds; in cardiac fibroblasts, it is expressed at low levels and restricts baseline TGF-β signaling. In pathological states, CELF4 exhibits context-dependent bidirectional modulation: in autism spectrum disorder (ASD), major depressive disorder (MDD), epilepsy, chronic pain, and endometrial cancer, its downregulation or epigenetic silencing causes translational derepression of target mRNAs; in cardiac fibrosis, TGF-β1-induced upregulation suppresses FMO2 translation and activates the Smad2/3 pathway. Additionally, pleiotropic genetic loci near CELF4 have been linked to gut-brain axis comorbidities and obesity-hypertension syndromes. Clinically, CELF4 promoter methylation testing has entered validation trials for non-invasive endometrial cancer screening, and its haploinsufficiency has been incorporated into the genetic diagnosis of 18q12.2 microdeletion syndrome; pharmacological and gene-replacement strategies targeting CELF4 remain at the preclinical proof-of-concept stage. Here, we review the molecular regulatory networks of CELF4 and its mechanisms across multisystem diseases, discuss the current status and limitations of clinical translation, and may guide future research on diagnostic biomarkers and therapeutic strategies targeting this protein.
Post-transcriptional regulation of gene expression has emerged as a fundamental determinant of cancer initiation, progression, and therapeutic response. Among the RNA-binding proteins (RBPs) involved in mRNA turnover and translational regulation, tristetraprolin (TTP), encoded by the ZFP36 gene, and “Human antigen R” (HuR), encoded by ELAVL1, represent two functionally antagonistic regulators of AU-rich element (ARE)-containing transcripts. TTP promotes the degradation of target mRNAs through recruitment of deadenylation and decay complexes, whereas HuR generally stabilizes and enhances the translation of overlapping mRNA subsets. Because many oncogenic, inflammatory, angiogenic, and metastasis-associated transcripts contain AREs within their 3′ untranslated regions, the balance between TTP-mediated decay and HuR-mediated stabilization critically influences tumor biology. Accumulating evidence demonstrates that loss of TTP expression or activity and cytoplasmic accumulation of HuR are recurrent features across multiple cancer types, including breast, colorectal, pancreatic, gastric, liver, ovarian, and lung cancers. Importantly, several studies indicate that the reciprocal interplay between these proteins establishes a post-transcriptional rheostat controlling cancer-associated RNA regulons. This review summarizes current knowledge regarding the molecular biology of TTP and HuR, emphasizing their opposing functions in mRNA metabolism and cancer progression. We discuss mechanisms regulating their expression, localization, phosphorylation, and RNA-binding activity; analyze cancer-specific evidence; and examine models in which both proteins are co-expressed or functionally interconnected. Finally, we evaluate therapeutic strategies aimed at restoring TTP function or inhibiting HuR activity and discuss future perspectives for targeting post-transcriptional regulatory networks in oncology.
R. Lotti, Tommaso Selmi, Alexis Grande et al.· Frontiers in Oncology· 0 citations
The molecular characteristics and pathological mechanisms of RBM47 are summarized, the preclinical rationale for its potential utility as a biomarker and therapeutic node is discussed, and current research limitations, conflicting evidence, and translational bottlenecks are critically analyzed.
Shihua Huang, Qingsong Wang, Junhong Shen et al.· Frontiers in Immunology· 0 citations
This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology.
A mechanism-driven approach is adopted to systematically examine SNHG1 dysregulation and its roles in cancer, which complements existing literature and provides a clear framework for future SNHG1 research.
Hao Zhou, Jianlin Zhou, Lin Zhou· Biocell (Mendoza)· 0 citations
Y-box binding protein 1 (YBX1) has been implicated across an unusually broad range of malignancies and processes: immune remodeling, epithelial plasticity, metabolic rewiring, epitranscriptomic reading, and resistance to chemotherapy, targeted agents, and checkpoint blockade. A linear one-gene/one-pathway oncogene model does not readily accommodate this breadth. We argue that the apparent diffuseness reflects a context-dependent regulatory node rather than experimental noise, and develop the hypothesis that YBX1 acts as an
adaptive RNA/transcriptional hub
, a regulator whose transcript outputs are set by cellular state rather than by a fixed binding program, which acts in both the transcriptional and post-transcriptional compartments, and which sits inside feedback loops linking downstream metabolic states back to its own activity. We organize the literature into three coupled layers: a state code, in which post-translational modifications, ubiquitin balance, localization, and phase separation determine which YBX1 is active (Layer 1); an RNA program, in which m5C reading and non-coding-RNA scaffolds are associated with a restricted survival transcriptome (Layer 2); and the immune, metabolic, and plasticity phenotypes these outputs generate (Layer 3). Evidence further suggests that tumor-specific dependency is carried by the configuration of the YBX1/YBX2/YBX3 family rather than by any single member. We specify what would falsify the framework: if state-resolved readouts do not predict downstream circuit activity better than total YBX1 abundance, the hub reduces to a promiscuous, abundant RNA-binding protein whose correlations are epiphenomenal. We give explicit weight to evidence resisting an oncogenic reading: circuits in which restraining YBX1 is tumor-suppressive, non-coding-RNA and family-level interactions running in opposite directions, and effectors regulated divergently between tumors, treating these as boundary conditions rather than exceptions. This reframing shifts the actionable question from whether YBX1 is high to which YBX1-dependent circuit a tumor uses; its value remains contingent on prospective, state- and circuit-level validation.
This work discusses new discoveries which highlight the value of lncRNA targeting as therapeutic applications, in gastrointestinal inflammation and cancer angiogenesis, and identifies gaps in the current knowledge and understanding.
Charlie Leboff, Pamela Calle-Mendoza, M. Hatziapostolou et al.· British Journal of Pharmacol...· 0 citations
