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Title 

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Authors 

J LeeK S FarquharJieun YunC A FrankenbergerE BevilacquaK YeungE J KimG BalazsiM R Rosner

Publisher 

National Academy of Sciences

Issue Date 

2014

Citation 

Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 3, pp. E364-E373

Keywords 

DynamicsEZH2HDACMathematical model

Abstract 

The sources and consequences of nongenetic variability in metastatic progression are largely unknown. To address these questions, we characterized a transcriptional regulatory network for the metastasis suppressor Raf kinase inhibitory protein (RKIP). We previously showed that the transcription factor BACH1 is negatively regulated by RKIP and promotes breast cancer metastasis. Here we demonstrate that BACH1 acts in a double-negative (overall positive) feedback loop to inhibit RKIP transcription in breast cancer cells. BACH1 also negatively regulates its own transcription. Analysis of the BACH1 network reveals the existence of an inverse relationship between BACH1 and RKIP involving both monostable and bistable transitions that can potentially give rise to nongenetic variability. Single-cell analysis confirmed monostable and bistablelike behavior. Treatment with histone deacetylase inhibitors or depletion of the polycomb repressor enhancer of zeste homolog 2 altered relative RKIP and BACH1 levels in a manner consistent with a prometastatic state. Together, our results suggest that the mutually repressive relationship between metastatic regulators such as RKIP and BACH1 can play a key role in determining metastatic progression in cancer.

ISSN 

0027-8424

Link 

http://dx.doi.org/10.1073/pnas.1304840111/-/DCSupplemental

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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