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

Jiyoung Lee, Jinho Lee, Kevin S. Farquhar, Jieun Yun, Casey A. Frankenberger, Elena Bevilacqua, Kam Yeung, Eun Jin Kim, Gábor Balázsi, Marsha Rich Rosner

Research output: Contribution to journalArticlepeer-review

112 Citations (Scopus)
52 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)E364–E373
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
Early online date6 Jan 2014
Publication statusPublished - 21 Jan 2014
Externally publishedYes

Bibliographical note

Freely available online through the PNAS open access option.


  • Dynamics
  • EZH2
  • HDAC
  • Mathematical model

ASJC Scopus subject areas

  • General


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