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Restoration of the molecular clock is tumor suppressive in neuroblastoma

Author

Listed:
  • Myrthala Moreno-Smith

    (Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine)

  • Giorgio Milazzo

    (University of Bologna)

  • Ling Tao

    (Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine)

  • Baharan Fekry

    (McGovern Medical School at the University of Texas Health Science Center (UT Health))

  • Bokai Zhu

    (University of Pittsburgh School of Medicine)

  • Mahmoud A. Mohammad

    (Agricultural Research Service, Baylor College of Medicine)

  • Simone Giacomo

    (University of Bologna)

  • Roshan Borkar

    (Baylor College of Medicine)

  • Karthik Reddy Kami Reddy

    (Baylor College of Medicine)

  • Mario Capasso

    (Università degli Studi di Napoli
    CEINGE Biotecnologie Avanzate)

  • Sanjeev A. Vasudevan

    (Baylor College of Medicine)

  • Pavel Sumazin

    (Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine)

  • John Hicks

    (Baylor College of Medicine)

  • Nagireddy Putluri

    (Baylor College of Medicine)

  • Giovanni Perini

    (University of Bologna)

  • Kristin Eckel-Mahan

    (McGovern Medical School at the University of Texas Health Science Center (UT Health))

  • Thomas P. Burris

    (Washington University School of Medicine and St. Louis College of Pharmacy)

  • Eveline Barbieri

    (Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Centers, Baylor College of Medicine)

Abstract

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic overexpression and its stimulation through the agonist SR1078, restores BMAL1 expression and oscillation, effectively blocks MYCN-mediated tumor growth and de novo lipogenesis, and sensitizes NB tumors to conventional chemotherapy. In conclusion, reactivation of RORα could serve as a therapeutic strategy for MYCN-amplified NBs by blocking the dysregulation of molecular clock and cell metabolism mediated by MYCN.

Suggested Citation

  • Myrthala Moreno-Smith & Giorgio Milazzo & Ling Tao & Baharan Fekry & Bokai Zhu & Mahmoud A. Mohammad & Simone Giacomo & Roshan Borkar & Karthik Reddy Kami Reddy & Mario Capasso & Sanjeev A. Vasudevan , 2021. "Restoration of the molecular clock is tumor suppressive in neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24196-4
    DOI: 10.1038/s41467-021-24196-4
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    Cited by:

    1. Ingrid M. Saldana-Guerrero & Luis F. Montano-Gutierrez & Katy Boswell & Christoph Hafemeister & Evon Poon & Lisa E. Shaw & Dylan Stavish & Rebecca A. Lea & Sara Wernig-Zorc & Eva Bozsaky & Irfete S. F, 2024. "A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    2. Ling Tao & Mahmoud A. Mohammad & Giorgio Milazzo & Myrthala Moreno-Smith & Tajhal D. Patel & Barry Zorman & Andrew Badachhape & Blanca E. Hernandez & Amber B. Wolf & Zihua Zeng & Jennifer H. Foster & , 2022. "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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