Restoration of the molecular clock is tumor suppressive in neuroblastoma

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, Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini, Kristin Eckel-Mahan, Thomas P. Burris and Eveline Barbieri ()
Additional contact information
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24196-4

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