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

Brajendra K. Tripathi (), Meghan F. Anderman, Disha Bhargava, Luciarita Boccuzzi, Xiaolan Qian, Dunrui Wang, Marian E. Durkin, Alex G. Papageorge, Fernando J. Miguel, Katerina Politi, Kylie J. Walters, James H. Doroshow and Douglas R. Lowy ()
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Brajendra K. Tripathi: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Meghan F. Anderman: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Disha Bhargava: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Luciarita Boccuzzi: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Xiaolan Qian: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Dunrui Wang: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Marian E. Durkin: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Alex G. Papageorge: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute
Fernando J. Miguel: Yale Cancer Center, Yale School of Medicine
Katerina Politi: Yale Cancer Center, Yale School of Medicine
Kylie J. Walters: Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
James H. Doroshow: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
Douglas R. Lowy: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26993-3

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