This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks, and assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity.
Abstract
Transcription factors (TFs) occupy a central position in cancer biology, functioning as master regulators that translate genetic, epigenetic and environmental cues into cell fate decisions, proliferation, survival, and therapy response. Historically deemed "undruggable" owing to their lack of catalytic sites, conformational flexibility, and engagement in broad protein-DNA and protein-protein interfaces, TFs were long considered beyond the reach of conventional pharmacology. Over the past decades, advances in structural biology, chemical biology, epigenetics, and nucleic acid therapeutics have begun to overcome these challenges, revealing actionable vulnerabilities within TF networks. This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks. It further assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity, encompassing direct inhibition, targeted protein degradation, modulation of TF-cofactor interactions, and nucleic acid-based interventions. We further highlight exemplary TFs and their typical targeting strategies, including Myelocytomatosis oncogene (MYC), Signal transducer and activator of transcription 3 (STAT3), Catenin beta-1 (β-catenin), Yes-associated protein/Transcriptional coactivator with PDZ-binding motif/Transcriptional enhanced associate domain (YAP/TAZ/TEAD), Estrogen receptor/Androgen receptor (ER/AR), and Phosphatase and tensin homolog/Protein kinase B/Forkhead box O (PTEN/AKT/FOXO), which illustrating mechanistic understanding of transcriptional regulation drives therapeutic development and enables genomics-guided precision oncology. By unifying mechanistic insight with pharmacological innovation, we aim to provide a conceptual framework for targeting the transcriptional architecture of cancer and charting paths toward next-generation transcription-directed therapies.
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.
BACKGROUND
Cyclin-dependent kinase 9 (CDK9) is a central regulator of RNA polymerase II elongation and has emerged as a therapeutic target in tumors characterized by transcriptional addiction. Growing interest in selective inhibitors and targeted degraders has renewed attention to the translational potential of CDK9-directed therapy.
AREAS COVERED
This review summarizes the molecular functions of the CDK9/positive transcription elongation factor b (P-TEFb) axis, its role in super-enhancer-driven oncogenic programs, and the mechanisms by which CDK9 inhibition promotes apoptosis, epigenetic derepression, and tumor microenvironment remodeling. We also discuss representative small-molecule inhibitors and proteolysis-targeting chimera (PROTAC) degraders, emerging biomarkers for patient stratification, rational combination strategies, and the current landscape of resistance mechanisms.
EXPERT OPINION
Selective targeting of CDK9 offers a promising route for treating refractory malignancies, particularly when guided by transcriptional dependency, biomarker-informed dosing, and rational combination design. Future progress will likely depend on improving therapeutic index, refining translational biomarkers, and anticipating adaptive resistance during clinical development.
Tiyao Liu, Zhongran Liu, Wen-Jing Wei et al.· Expert opinion on therapeuti...· 0 citations
This review presents an in-depth analysis of the most recent advances in small-molecule epigenetic modulators, focusing on their mechanisms of action, therapeutic applications, and the challenges impeding their clinical development, with the aim of informing the rational design and optimization of next-generation epigenetic treatment strategies for cancer.
Peng Jin, Yi Wang, Na Zhao et al.· Biochimica et biophysica act...· 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
Cancer remains a major global health burden, with its incidence and mortality rates persistently high despite advances in treatment. Despite therapeutic innovations, malignant tumors continue to pose a formidable challenge to global health. Against this backdrop, the crosstalk between long non-coding RNAs (lncRNAs) and the Notch signaling pathway has emerged as a pivotal driver of tumorigenesis and progression. However, the complex regulatory network and a comprehensive mechanistic framework of this axis await systematic elucidation. This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication. The discussion encompasses various malignancies, spanning the digestive, respiratory, urogenital, nervous, and hematologic systems. The lncRNA-Notch regulatory axis is identified as a ubiquitous and functionally central oncogenic network. It orchestrates critical malignant phenotypes—such as such as stemness maintenance, epithelial-mesenchymal transition, metabolic shifts, drug resistance, and immune evasion—through intricate bidirectional crosstalk. Functional studies confirm that targeting key nodes of this axis can effectively reverse drug resistance and suppress tumor growth. Although challenges remain in its clinical translation, future research integrating single-cell multi-omics, nanotechnology, and other innovative strategies will undoubtedly open new avenues for precision diagnosis and cancer therapy.
Qing-miao Shi, Na Lou, Huiwu Xing et al.· Frontiers in Cell and Develo...· 0 citations
Epigenetic modifications play a crucial role in cancer, influencing cellular physiology, extracellular matrix (ECM) remodeling, and immune responses. With growing emphasis on chromatin remodeling and the epigenetic regulation of immunity, these regulatory pathways and related players have become focal points of oncological investigations. Epigenetic manipulation of immune system components has emerged as a promising strategy in cancer treatment. Several FDA-approved "epi-drugs" target the epigenome to modulate immune responses and offer new opportunities across different cancers. DNA repair pathways contribute significantly to the avoidance of cancer initiation and also contribute to cellular resistance in cancer treatment. Chromatin remodelers such as INO80, Fun30, and RAD54 play essential roles in DNA damage response (DDR) through homologous recombination and non-homologous end-joining pathways, and their dysregulation leads to genome instability and tumor progression. Chromatin remodeling complexes, including SWI/SNF and CHD families, are frequently altered across various cancer types, further highlighting their role in cancer pathophysiology. Targeting these chromatin modifiers and associated DNA repair mechanisms may provide novel therapeutic options. In addition, combining epigenetic modulators with immunotherapies has shown promise in enhancing responses to immune checkpoint blockade. Epigenetic drugs such as histone deacetylase (HDAC) inhibitors and DNA methylation inhibitors are being explored for their synergistic effects with immunotherapy. While the interplay between chromatin remodeling, DNA repair, and immune responses provides a strong framework for developing targeted oncological strategies, further research is required to better understand these interactions and optimize their clinical application.
S. Riaz, Mehwish Iqbal, Farwa Tahir et al.· Molecular Medicine· 0 citations
