EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

Nature Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 384 - 399

Published: Feb. 24, 2022

Language: Английский

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DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting

Accounts of Chemical Research, Journal Year: 2022, Volume and Issue: 55(18), P. 2628 - 2646

Published: Sept. 2, 2022

DNA G-quadruplex secondary structures formed in guanine-rich human telomeres and oncogene promoters are functionally important have emerged as a promising new class of cancer-specific drug targets. These globular intramolecular stabilized by K+ or Na+ form readily under physiological solution conditions. Moreover, G-quadruplexes epigenetic features can alter chromatin structure function together with interactive proteins. Here, we discuss our efforts over the last two decades to understand functions key their interactions small molecules. Using high-field NMR spectroscopy, determined high-resolution physiologically relevant telomeric major (hybrid-2) minor (hybrid-1), well two-tetrad intermediate. The intrinsic structural polymorphism may be for biology telomeres, proposed model interconversion. More recently, worked on MYC, BCL2, PDGFR-β, VEGF, k-RAS promoters. We MYC promoter, prototype parallel G-quadruplexes. It is first example parallel-stranded G3NG3 motif 1-nt loop, which prevalent promoter sequences likely evolutionarily selected initiate folding. Remarkably, highly stable. Additionally, molecular PDGFR-β promoters, each adopting unique structure. For example, BCL2 contains distinct interchangeable adjacent regions, suggesting precise regulation different adopts "broken-strand" vacancy G-quadruplexes, recognized cellular guanine metabolites potential regulatory role.Structural information complex small-molecules critical understanding specific recognition structure-based rational design. Our studies show that many contain such capping loop structures, allowing drugs protein. This represents paradigm shift target: Rather than uniform, nonselective binding site duplex DNA, being pursued selectively targetable receptors. focus targeting biologically (MycG4) molecules its additional structures. Very discovered clinically tested indenoisoquinolines strong MycG4 binders potent inhibitors. also dGMP-bound-vG4 promoter. specifically recognize Unlike previously dogma optimal ligands large aromatic cyclic compounds, results suggest smaller asymmetric compounds appropriate functional groups better choices bind body work lays foundation future aimed at G-quadruplex-targeted

Language: Английский

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MYC: a complex problem

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(3), P. 235 - 246

Published: Aug. 10, 2022

The MYC protooncogene functions as a universal amplifier of transcription through interaction with numerous factors and complexes that regulate almost every cellular process. However, comprehensive model explains MYC's actions the interplay governing complicated dynamics components replication machinery is still lacking. Here, we review potency an oncogenic driver how it regulates broad spectrum (effectors regulators). We propose 'hand-over model' for differential partitioning trafficking unstructured via loose network between various gene-regulatory factors. Additionally, article discusses unstructured-MYC energetically favors efficient modulation energy landscape cycle.

Language: Английский

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Integrins in cancer: Emerging mechanisms and therapeutic opportunities

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 247, P. 108458 - 108458

Published: May 27, 2023

Integrins are vital surface adhesion receptors that mediate the interactions between extracellular matrix (ECM) and cells essential for cell migration maintenance of tissue homeostasis. Aberrant integrin activation promotes initial tumor formation, growth, metastasis. Recently, many lines evidence have indicated integrins highly expressed in numerous cancer types documented functions tumorigenesis. Thus, emerged as attractive targets development therapeutics. In this review, we discuss underlying molecular mechanisms by which contribute to most hallmarks cancer. We focus on recent progress regulators, binding proteins, downstream effectors. highlight role regulation metastasis, immune evasion, metabolic reprogramming, other addition, integrin-targeted immunotherapy inhibitors been used preclinical clinical studies summarized.

Language: Английский

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Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis

Cell Death and Differentiation, Journal Year: 2022, Volume and Issue: 29(9), P. 1864 - 1873

Published: March 16, 2022

Language: Английский

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MYC multimers shield stalled replication forks from RNA polymerase

Nature, Journal Year: 2022, Volume and Issue: 612(7938), P. 148 - 155

Published: Nov. 23, 2022

Language: Английский

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The homeostatic regulation of ribosome biogenesis

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 136, P. 13 - 26

Published: April 16, 2022

Language: Английский

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BRD4 and MYC: power couple in transcription and disease

FEBS Journal, Journal Year: 2022, Volume and Issue: 290(20), P. 4820 - 4842

Published: July 22, 2022

The MYC proto‐oncogene and BRD4, a BET family protein, are two cardinal proteins that have broad influence in cell biology disease. Both expressed ubiquitously mammalian cells play central roles controlling growth, development, stress responses metabolic function. As chromatin transcriptional regulators, they critical role regulating the expression of burgeoning array genes, maintaining architecture genome stability. Consequently, impairment their function or regulation leads to many diseases, with cancer being most predominant. Interestingly, accumulating evidence indicates functions tightly intertwined BRD4 at both post‐transcriptional levels. Here, we review mechanisms by which regulated, governing various molecular consequences dysregulation lead We present perspective how regulatory for could be entwined multiple points BRD4‐MYC nexus modulation disease upon dysregulation.

Language: Английский

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Orphan quality control shapes network dynamics and gene expression

Cell, Journal Year: 2023, Volume and Issue: 186(16), P. 3460 - 3475.e23

Published: July 20, 2023

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex are established remains poorly understood. Here, we identify E3 ligase UBR5 as a signaling hub helps degrade unpaired subunits multiple transcriptional regulators act within centered on c-Myc oncoprotein. Biochemical structural analyses show binds motifs only become available upon dissociation. By rapidly turning over transcription factor subunits, establishes dynamic allow cells effectively execute gene expression while remaining receptive environmental signals. We conclude orphan quality control plays an essential role establishing networks, which may explain conserved need for degradation during offers opportunities modulate disease.

Language: Английский

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Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis

Pharmacological Research, Journal Year: 2023, Volume and Issue: 188, P. 106668 - 106668

Published: Jan. 18, 2023

Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with osimertinib who regained positive response after plus anlotinib treatment. Two osimertinib-resistant lines were constructed, and AXL conferred to NSCLC lines. The combined effects restored sensitivity two xenografts. Moreover, inhibits phosphorylation both resistant Mechanistically, confirmed MYC binds promoter promote its transcription cells, demonstrated treatment enhances anti-tumor effect by inactivating c-MET/MYC/AXL axis reverse NSCLC. conclusion, our results provide strong support therapy may effective enhancing

Language: Английский

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