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

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Title
Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions
Author(s)
J Lee; J Lee; K S Farquhar; Jieun Yun; C A Frankenberger; E Bevilacqua; K Yeung; E J Kim; G Balazsi; M R Rosner
Bibliographic Citation
Proceedings of National Academy of Sciences of United States of America, vol. 111, no. 3, pp. E364-E373
Publication Year
2014
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.
Keyword
DynamicsEZH2HDACMathematical model
ISSN
0027-8424
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.1304840111
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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