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Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essential. Here, we identified that an underappreciated serine/threonine kinase, cyclin-dependent kinase-like 3 (CDKL3), crucially drives rapid cell cycle progression and cell growth in cancers. With regard to mechanism, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of cyclin-dependent kinase 4 (CDK4) by direct phosphorylation on T172 to sustain [G.sub.1] phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized, and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes acquired resistance to CDK4/6 inhibitor. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presents an integrated paradigm of cancer cell cycle regulation and suggests CDKL3 targeting as a feasible approach in cancer treatment., Introduction The cell cycle consists of multiple modules and machineries to regulate cell division in a precise manner (1, 2). A complete cell cycle is composed of [G.sub.1], S, [G.sub.2], [...]

It is a considerable challenge to develop surface-enhanced Raman spectroscopy sensors with high sensitivity but a lack of selective recognition performance for target species in the applied field. Here, a strategy for fabricating a meso-Au/BN nanoparticle (NP) sensor through a synthesized mesoporous Au NPs' surface modified by BN quantum dots (QDs) and 2-mercaptoethylamine (MEA) through electrostatic attraction and covalent bonding between a sulfur atom in the thiol group and an Au atom, respectively, was implemented to selectively recognize and sensitively detect 2,4,6-trinitrotoluene (TNT). TNT interacted with MEA on the meso-Au NP surface to form a TNT–MEA complex through the electrostatic affinity interaction between the electron-deficient nitro groups and the electron-rich amino group at the fluorescence-tagged sites, approaching the BN QDs on the meso-Au NPs' surface at spatial proximity, leading to the suppression of the fluorescence intensity of BN QDs via the fluorescence resonance energy transfer mechanism, forming the selective recognition of TNT. Additionally, the meso-Au/BN NP sensor enhanced the Raman signal of TNT by the localized surface plasmon resonance hotspots of the meso-Au NP surface, achieving highly sensitive detection of TNT. The limit of detection for TNT was 10–9 mol·L–1. Comparing TNT, 2,4-dinitrotoluene, 2,4,6-trinitrophenol, and 2,4-dinitrophenol, the meso-Au/BN NP sensor exhibited much more selective recognition and sensitive detection of TNT than other aromatic compounds. The method can be widely applied in the selective recognition and trace detection of biological molecules, metal ions, and organic pollutants. [ABSTRACT FROM AUTHOR]

Background and Aims: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy., Approach and Results: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC., Conclusions: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment., (Copyright © 2024 American Association for the Study of Liver Diseases.)