Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1

Sarah Javaid; Jianmin Zhang; Endre Anderssen; Joshua C. Black; Ben S. Wittner; Ken Tajima; David T. Ting; Gromoslaw A. Smolen; Matthew Zubrowski; Rushil Desai; Shyamala Maheswaran; Sridhar Ramaswamy; Johnathan R. Whetstine; Daniel A. Haber

doi:10.1016/j.celrep.2013.11.034

Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1

Sarah Javaid, Jianmin Zhang, Endre Anderssen, Joshua C. Black, Ben S. Wittner, Ken Tajima, David T. Ting, Gromoslaw A. Smolen, Matthew Zubrowski, Rushil Desai, Shyamala Maheswaran, Sridhar Ramaswamy, Johnathan R. Whetstine, Daniel A. Haber

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Abstract

Epithelial-mesenchymal transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. After Snail-1 induction, epithelial markers were repressed within 6hr, and mesenchymal genes were induced at 24hr. Snail-1 binding to its target promoters was transient (6-48hr) despite continued protein expression, and it was followed by both transient and long-lasting chromatin changes. Pharmacological inhibition of selected histone acetylation and demethylation pathways suppressed the induction as well as the maintenance of Snail-1-mediated EMT. Thus, EMT involves an epigenetic switch that may be prevented or reversed with the use of small-molecule inhibitors of chromatin modifiers.

Original language	English
Pages (from-to)	1679-1689
Number of pages	11
Journal	Cell Reports
Volume	5
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2013.11.034
State	Published - Dec 26 2013

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Javaid, S., Zhang, J., Anderssen, E., Black, J. C., Wittner, B. S., Tajima, K., Ting, D. T., Smolen, G. A., Zubrowski, M., Desai, R., Maheswaran, S., Ramaswamy, S., Whetstine, J. R., & Haber, D. A. (2013). Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1. Cell Reports, 5(6), 1679-1689. https://doi.org/10.1016/j.celrep.2013.11.034

@article{daebb47122d348238eb2451cd1ad3819,

title = "Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1",

abstract = "Epithelial-mesenchymal transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. After Snail-1 induction, epithelial markers were repressed within 6hr, and mesenchymal genes were induced at 24hr. Snail-1 binding to its target promoters was transient (6-48hr) despite continued protein expression, and it was followed by both transient and long-lasting chromatin changes. Pharmacological inhibition of selected histone acetylation and demethylation pathways suppressed the induction as well as the maintenance of Snail-1-mediated EMT. Thus, EMT involves an epigenetic switch that may be prevented or reversed with the use of small-molecule inhibitors of chromatin modifiers.",

author = "Sarah Javaid and Jianmin Zhang and Endre Anderssen and Black, {Joshua C.} and Wittner, {Ben S.} and Ken Tajima and Ting, {David T.} and Smolen, {Gromoslaw A.} and Matthew Zubrowski and Rushil Desai and Shyamala Maheswaran and Sridhar Ramaswamy and Whetstine, {Johnathan R.} and Haber, {Daniel A.}",

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doi = "10.1016/j.celrep.2013.11.034",

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Javaid, S, Zhang, J, Anderssen, E, Black, JC, Wittner, BS, Tajima, K, Ting, DT, Smolen, GA, Zubrowski, M, Desai, R, Maheswaran, S, Ramaswamy, S, Whetstine, JR & Haber, DA 2013, 'Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1', Cell Reports, vol. 5, no. 6, pp. 1679-1689. https://doi.org/10.1016/j.celrep.2013.11.034

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T1 - Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1

AU - Javaid, Sarah

AU - Zhang, Jianmin

AU - Anderssen, Endre

AU - Black, Joshua C.

AU - Wittner, Ben S.

AU - Tajima, Ken

AU - Ting, David T.

AU - Smolen, Gromoslaw A.

AU - Zubrowski, Matthew

AU - Desai, Rushil

AU - Maheswaran, Shyamala

AU - Ramaswamy, Sridhar

AU - Whetstine, Johnathan R.

AU - Haber, Daniel A.

PY - 2013/12/26

Y1 - 2013/12/26

N2 - Epithelial-mesenchymal transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. After Snail-1 induction, epithelial markers were repressed within 6hr, and mesenchymal genes were induced at 24hr. Snail-1 binding to its target promoters was transient (6-48hr) despite continued protein expression, and it was followed by both transient and long-lasting chromatin changes. Pharmacological inhibition of selected histone acetylation and demethylation pathways suppressed the induction as well as the maintenance of Snail-1-mediated EMT. Thus, EMT involves an epigenetic switch that may be prevented or reversed with the use of small-molecule inhibitors of chromatin modifiers.

AB - Epithelial-mesenchymal transition (EMT) is thought to contribute to cancer metastasis, but its underlying mechanisms are not well understood. To define early steps in this cellular transformation, we analyzed human mammary epithelial cells with tightly regulated expression of Snail-1, a master regulator of EMT. After Snail-1 induction, epithelial markers were repressed within 6hr, and mesenchymal genes were induced at 24hr. Snail-1 binding to its target promoters was transient (6-48hr) despite continued protein expression, and it was followed by both transient and long-lasting chromatin changes. Pharmacological inhibition of selected histone acetylation and demethylation pathways suppressed the induction as well as the maintenance of Snail-1-mediated EMT. Thus, EMT involves an epigenetic switch that may be prevented or reversed with the use of small-molecule inhibitors of chromatin modifiers.

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DO - 10.1016/j.celrep.2013.11.034

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VL - 5

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JO - Cell Reports

JF - Cell Reports

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Dynamic chromatin modification sustains epithelial-mesenchymal transition following inducible expression of snail-1

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