한빛사논문
- 조회2,721
Abstract
Jiyoung Leea, Jinho Leeb, Kevin S. Farquharb, Jieun Yuna,c, Casey A. Frankenbergera, Elena Bevilacquaa, Kam Yeungd, Eun-Jin Kime, Gábor Balázsib,1, and Marsha Rich Rosnera,1
aBen May Department for Cancer Research, The University of Chicago, Chicago, IL 60637;
bDepartment of Systems Biology–Unit 950, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
cBioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 363-883, Korea;
dDepartment of Biochemistry and Cancer Biology, The University of Toledo, Toledo, OH 43606; and
eSchool of Mathematics and Statistics, University of Sheffield, Sheffield S3 7RH, United Kingdom
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.
HDAC, EZH2, mathematical model, dynamics
1To whom correspondence may be addressed.
Author contributions: G.B. and M.R.R. designed research; Jiyoung Lee, Jinho Lee, K.S.F., J.Y., C.A.F., E.-J.K., and G.B. performed research; K.Y. contributed new reagents/analytic tools; Jiyoung Lee, G.B., and M.R.R. analyzed data; and Jiyoung Lee, E.B., G.B., and M.R.R. wrote the paper.
논문정보
- Research article
- 2014년 01월 (BRIC 등록일 2014-01-10)
- 국내+국외 연구진
댓글 작성 로그인
팝업 닫기관련 링크
