2. Academic Validation
  3. Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein

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

  • Nat Commun. 2021 Dec 3;12(1):6941. doi: 10.1038/s41467-021-26993-3.
Brajendra K Tripathi 1,  Meghan F Anderman 2,  Disha Bhargava 2,  Luciarita Boccuzzi 2,  Xiaolan Qian 2,  Dunrui Wang 2,  Marian E Durkin 2,  Alex G Papageorge 2,  Fernando J de Miguel 3,  Katerina Politi 3 4,  Kylie J Walters 5,  James H Doroshow 6,  Douglas R Lowy 7
Affiliations

Affiliations

  • 1 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. [email protected].
  • 2 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 3 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
  • 4 Departments of Pathology and Internal Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT, USA.
  • 5 Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • 6 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 7 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. [email protected].
PMID: 34862367 DOI: 10.1038/s41467-021-26993-3
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.

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