TY - JOUR
T1 - Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma
AU - Jiang, Haowen
AU - Greathouse, Rachel L.
AU - Tiche, Sarah Jane
AU - Zhao, Man
AU - He, Bo
AU - Li, Yang
AU - Li, Albert M.
AU - Forgo, Balint
AU - Yip, Michaela
AU - Li, Allison
AU - Shih, Moriah
AU - Banuelos, Selene
AU - Zhou, Meng Ning
AU - Gruber, Joshua J.
AU - Rankin, Erinn B.
AU - Hu, Zhen
AU - Shimada, Hiroyuki
AU - Chiu, Bill
AU - Ye, Jiangbin
N1 - Funding Information:
H. Jiang reports a patent for US20220175704A1 pending. Y. Li reports a patent for US20220175704A1 pending. J.J. Gruber reports grants from Hummingbird Bioscience and personal fees from Guidepoint and Sharma Therapeutics outside the submitted work. B. Chiu reports grants from NIH during the conduct of the
Funding Information:
This work was supported by a Stanford Maternal and Child Health Research Institute Research Scholar Award (2020) and an American Cancer Society Research Scholar Grant (RSG-20–036–01 to J. Ye) and NIH funding (R01NS094218 to B. Chiu). The authors thank Dr. Yuqin Dai (Stanford ChEM-H Institute Metabolomics Knowledge Center) for support and use of facilities, Vanita S. Natu (Stanford Genomics) for providing Infinium MethylationEPIC analysis service, Drs. Maximilian Diehn, Beverly S. Mitchell, Laura Attardi, and Roeland Nusse (Stanford University) for valuable advice and suggestions, and John M. Snyder (Radiation Oncology) for support on statistical analysis.
Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2023/1/15
Y1 - 2023/1/15
N2 - The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NADþ/NADH and pyruvate/lactate ratios and also the a-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and b-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and b-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.
AB - The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NADþ/NADH and pyruvate/lactate ratios and also the a-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and b-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and b-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.
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U2 - 10.1158/0008-5472.CAN-22-1029
DO - 10.1158/0008-5472.CAN-22-1029
M3 - Article
C2 - 36318118
AN - SCOPUS:85143309873
SN - 0008-5472
VL - 83
SP - 181
EP - 194
JO - Cancer research
JF - Cancer research
IS - 2
ER -