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 Di Giacomo, Roshan M. Borkar, Karthik Reddy Kami Reddy, Mario Capasso, Sanjeev A. Vasudevan, Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini, Kristin Eckel‐Mahan, Thomas P. Burris, Eveline Barbieri
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.