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Mol Cell. 2018 Oct 4;72(1):60-70.e3. doi: 10.1016/j.molcel.2018.08.025. Epub 2018 Sep 20.

A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network.

Author information

1
Yale Systems Biology Institute and Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21205, USA.
2
Department of Biomedical Engineering, Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21205, USA.
3
Department of Biomedical Engineering, Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. Electronic address: afeinberg@jhu.edu.
4
Yale Systems Biology Institute and Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21205, USA. Electronic address: andre.levchenko@yale.edu.

Abstract

Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans. However, the molecular underpinnings of the LOI phenotype are not clear. Surprisingly, in LOI cells, we find a reversal of the relative activities of two canonical signaling pathways triggered by IGF2, causing further rebalancing between pro- and anti-apoptotic signaling. A predictive mathematical model shows that this network rebalancing quantitatively accounts for the effect of receptor tyrosine kinase inhibition in both WT and LOI cells. This mechanism also quantitatively explains both the stable LOI phenotype and the therapeutic window for selective killing of LOI cells, and thus prevention of epigenetically controlled cancers. These findings suggest a framework for understanding epigenetically modified cell signaling.

KEYWORDS:

AKT; ERK; apoptosis; computational model; death plane; epigenetics; imprinting; kinase signaling; network rewiring; oncogene addiction

PMID:
30244832
PMCID:
PMC6219618
[Available on 2019-10-04]
DOI:
10.1016/j.molcel.2018.08.025
[Indexed for MEDLINE]

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