This review summarizes current knowledge regarding the molecular biology of TTP and HuR, emphasizing their opposing functions in mRNA metabolism and cancer progression; discusses mechanisms regulating their expression, localization, phosphorylation, and RNA-binding activity; analyze cancer-specific evidence; and examines models in which both proteins are co-expressed or functionally interconnected.
Abstract
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.
Findings highlight a HuR-SerpinB9 axis that regulates T-cell senescence and persistence, offering a potential therapeutic target in cancer and autoimmune diseases.
P. Chakraborty, Mrinmoyee Majumder, W. Wofford et al.· Journal of Immunology· 0 citations
ABSTRACT RNA‐binding proteins (RBPs) are central regulators of post‑transcriptional gene expression, controlling RNA stability, localization, translation, and alternative splicing. Their functions arise not only from intrinsic RNA‐binding domains but also from dynamic interactions with noncoding RNAs, metabolites, cofactors, and other RBPs. Here, we summarize the structural diversity and core biological activities of canonical and noncanonical RBPs, and delineate how competitive and cooperative regulatory networks dictate RBP function in disease, with an emphasis on cancer. Competitive mechanisms, including lncRNA‐mediated sequestration, antagonistic crosstalk between miRNAs and RBPs, and competition among RBPs for shared substrates, can redirect RNA fate. In contrast, cooperative mechanisms assemble multimolecular ribonucleoprotein complexes that reinforce oncogenic or tumor‐suppressive programs. Dysregulation of these networks promotes proliferation, metastasis, immune evasion, and therapy resistance. We also review emerging therapeutic strategies that target RBP‐centered regulatory circuits, including antisense oligonucleotides, small molecules, protein degraders, and natural products, and we evaluate representative preclinical studies and clinical trials. By integrating mechanistic principles with translational evidence, this review provides a network‐based framework for exploiting RBPs as therapeutic vulnerabilities and for advancing next‐generation precision oncology.
Ling Li, Xiu-Li Yan, Qing Ji et al.· MedComm· 0 citations
DExH-box helicase 9 (DHX9) is a multifunctional nucleic acid helicase that participates in R-loop homeostasis, genome maintenance, RNA metabolism, and innate immune signaling. Accumulating evidence has linked aberrant DHX9 expression or activity to tumorigenesis, tumor progression, treatment response, and patient prognosis. However, its role in cancer is highly context-dependent, rather than uniformly oncogenic or tumor suppressive. Depending on its molecular partners, subcellular localization, post-translational modifications, tumor genotype, and immune microenvironment, DHX9 may either promote malignant phenotypes or contribute to tumor-restraining processes. In this review, we summarize the molecular characteristics and regulatory properties of DHX9, discuss its roles in genome stability, transcriptional and post-transcriptional control, circular RNA (circRNA) biogenesis, and tumor-immune crosstalk, and evaluate its emerging value as a potential biomarker and therapeutic target. We also highlight key challenges in this field, including mechanistic heterogeneity, insufficient translational validation, and the urgent need for context-informed patient stratification to maximize the clinical utility of DHX9-targeted strategies.
Yejin Cai, Ziyuan Chen, Jiaying Xiong et al.· Biochimica et biophysica act...· 0 citations
Regulation of miRNAs in mammalian cells-including their expression, activity, transport, storage, and export-is vital for the control of gene expression and cellular function. This process is affected by external stimuli, such as stress or pathogen exposure, and regulated by interactions among miRNAs, target mRNAs, and RNA-binding proteins. Human ELAVL1 HuR, a stress-responsive nuclear protein that can shuttle to the cytoplasm, modulates miRNA activity, storage, and export in a contextual manner. As an AU-rich element (ARE)-containing RNA-binding protein, HuR plays multimodal roles in miRNA regulation. How HuR manages these diverse functions under stress, infection, or in cancer remains a key area of research. This review explores the miRNA-regulatory role of HuR across subcellular compartments, focusing on how its localization affects miRNA export or storage, and discusses potential mechanisms underlying HuR's versatile functions, including mRNA stabilization and miRNA homeostasis. This review discussed how post-translational modifications of HuR or its partners affect miRNA activity, suggesting that HuR serves as a miRNA sensor and linking HuR-related miRNA regulation to human diseases, thereby positioning HuR as a druggable target for controlling miRNA activity and target gene expression.
Kamalika Mukherjee· Biochimica et biophysica act...· 1 citation
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, Jian-Lin Zhou, Lin Zhou· Biocell (Mendoza)· 0 citations
Transcriptional dysregulation is a hallmark of cancer and is frequently driven by oncogenic alterations that rewire downstream gene-expression programmes. Although kinase inhibitors targeting upstream oncogenic drivers can produce clinical benefit, responses are often limited by acquired resistance and pathway adaptation. Targeting transcriptional dependencies therefore represents an alternative therapeutic strategy. The positive transcription elongation factor b complex, composed of CDK9 and Cyclin T1(CCNT1), is a central regulator of RNA polymerase II transcriptional elongation and supports the expression of genes required for tumour cell survival. However, conventional CDK9 inhibitors often lack sufficient selectivity and are associated with dose-limiting toxicities. Here, we report the rational design of a novel CCNT1-targeting binder and its application in biological proteolysis-targeting chimeras designed to selectively degrade Cyclin T1. The degrader platform combines E3 ubiquitin ligase recruitment with a dual-peptide CCNT1-binding module derived from the pTEFb-interacting partners AFF4 and HIV-TAT. This engineered recruitment strategy enabled robust and selective depletion of both tagged and endogenous CCNT1 in cancer cells. CCNT1 degradation was accompanied by destabilisation of its catalytic partner CDK9 and reduced phosphorylation of RNA polymerase II, consistent with suppression of transcriptional elongation. Functionally, CCNT1-targeted degradation produced marked anti-tumour effects in lung cancer models. Degrader-treated cells showed impaired proliferative capacity, reduced colony formation, cell-cycle disruption across multiple checkpoints, and induction of apoptosis. These findings demonstrate that selective degradation of CCNT1 can effectively collapse pTEFb-dependent transcriptional programmes and compromise tumour cell fitness. Together, our study establishes a novel CCNT1 binder-enabled degrader strategy as a translational approach to targeting transcriptional addiction in cancer. By moving beyond catalytic CDK9 inhibition and directly eliminating the Cyclin T1 scaffold, CCNT1-targeted degradation may offer a more selective and durable route for therapeutic intervention in transcriptionally dependent tumours.
Janice Wenzheng Neng, Laura Blenkarn, Laura S. Itzhaki, Catherine H. Wilson. Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR010.
Janice Wenzheng Neng, Laura Blenkarn, Laura S. Itzhaki et al.· Clinical Cancer Research· 0 citations
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