Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein

Autor: Katerina Politi, Disha Bhargava, Brajendra K. Tripathi, Meghan F. Anderman, Douglas R. Lowy, Alex G. Papageorge, Luciarita Boccuzzi, Xiaolan Qian, Dunrui Wang, Marian E. Durkin, James H. Doroshow, Fernando J. de Miguel, Kylie J. Walters
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Boron Compounds
Proteasome Endopeptidase Complex
Lung Neoplasms
Tumor suppressor gene
Science
Glycine
General Physics and Astronomy
Antineoplastic Agents
macromolecular substances
Methylation
General Biochemistry
Genetics and Molecular Biology
Article
Proto-Oncogene Proteins p21(ras)
Gene Knockout Techniques
Mice
Cell Line
Tumor
Histone methylation
Animals
Humans
Enhancer of Zeste Homolog 2 Protein
Benzodioxoles
Phosphorylation
Protein kinase B
Protein Kinase Inhibitors
Multidisciplinary
Chemistry
Kinase
Protein Stability
Tumor Suppressor Proteins
EZH2
fungi
GTPase-Activating Proteins
food and beverages
General Chemistry
Xenograft Model Antitumor Assays
HEK293 Cells
Gene Knockdown Techniques
Cancer research
Mutagenesis
Site-Directed
Quinazolines
DLC1
Non-small-cell lung cancer
Heterocyclic Compounds
3-Ring
Proteasome Inhibitors
Proto-oncogene tyrosine-protein kinase Src
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)
ISSN: 2041-1723
Popis: mRNA expression of the DLC1 tumor suppressor gene is downregulated in many lung cancers and their derived cell lines, with DLC1 protein levels being low or absent. Although the role of increased EZH2 methyltransferase in cancer is usually attributed to its histone methylation, we unexpectedly observed that post-translational destabilization of DLC1 protein is common and attributable to its methylation by cytoplasmic EZH2, leading to CUL-4A ubiquitin-dependent proteasomal degradation of DLC1. Furthermore, siRNA knockdown of KRAS in several lines increases DLC1 protein, associated with a drastic reduction in cytoplasmic EZH2. Pharmacologic inhibition of EZH2, CUL-4A, or the proteasome can increase the steady-state level of DLC1 protein, whose tumor suppressor activity is further increased by AKT and/or SRC kinase inhibitors, which reverse the direct phosphorylation of DLC1 by these kinases. These rational drug combinations induce potent tumor growth inhibition, with markers of apoptosis and senescence, that is highly dependent on DLC1 protein.
The tumor suppressor gene DLC1 can be downregulated in cancers through genetic and non-genetic mechanisms. Here, the authors show cytoplasmic EZH2 can directly methylate and destabilize the DLC1 protein, and EZH2 inhibition can increase the DLC1 protein half-life at least 20-fold.
Databáze: OpenAIRE
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