title: Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions.
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 bistable-like 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.
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Lee
authors.forename: Jinho
authors.initials: J
authors.lastname: Lee
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Farquhar
authors.forename: Jieun
authors.initials: J
authors.lastname: Yun
authors.forename: Casey A
authors.initials: CA
authors.lastname: Frankenberger
authors.forename: Elena
authors.initials: E
authors.lastname: Bevilacqua
authors.forename: Kam
authors.initials: K
authors.lastname: Yeung
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Gábor
authors.initials: G
authors.lastname: Balázsi
authors.forename: Marsha Rich
authors.initials: MR
authors.lastname: Rosner
mesh_terms: D020816:Amino Acid Motifs; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism*; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D061986:MCF-7 Cells; D008962:Models, Theoretical; D009362:Neoplasm Metastasis; D018384:Oxidative Stress; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein
keywords: EZH2; HDAC; dynamics; mathematical model