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

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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
    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)

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.

Suggested Citation

  • 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. , 2021. "Inhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26993-3
    DOI: 10.1038/s41467-021-26993-3
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    References listed on IDEAS

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    1. Talha Anwar & Caroline Arellano-Garcia & James Ropa & Yu-Chih Chen & Hong Sun Kim & Euisik Yoon & Sierrah Grigsby & Venkatesha Basrur & Alexey I. Nesvizhskii & Andrew Muntean & Maria E. Gonzalez & Kel, 2018. "p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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