Children’s Nutrition Research Center Staff Publications
Publication Date
6-28-2021
Journal
Nature Communications
DOI
10.1038/s41467-021-24196-4
PMID
34183658
PMCID
PMC8238982
PubMedCentral® Posted Date
6-28-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
ARNTL Transcription Factors, Animals, Antineoplastic Agents, Benzamides, Cell Line, Tumor, Cell Survival, Humans, Lipogenesis, Mice, N-Myc Proto-Oncogene Protein, Neuroblastoma, Nuclear Receptor Subfamily 1, Group F, Member 1, Promoter Regions, Genetic, Xenograft Model Antitumor Assays, Cancer, Cell biology
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.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons