P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis

Talha Anwar; Caroline Arellano-Garcia; James Ropa; Yu Chih Chen; Hong Sun Kim; Euisik Yoon; Sierrah Grigsby; Venkatesha Basrur; Alexey I. Nesvizhskii; Andrew Muntean; Maria E. Gonzalez; Kelley M. Kidwell; Zaneta Nikolovska-Coleska; Celina G. Kleer

doi:10.1038/s41467-018-05078-8

P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis

Talha Anwar, Caroline Arellano-Garcia, James Ropa, Yu Chih Chen, Hong Sun Kim, Euisik Yoon, Sierrah Grigsby, Venkatesha Basrur, Alexey I. Nesvizhskii, Andrew Muntean, Maria E. Gonzalez, Kelley M. Kidwell, Zaneta Nikolovska-Coleska, Celina G. Kleer

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.

Original language	English
Article number	2801
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05078-8
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
We thank members of the Kleer lab for discussions during the execution of this project. We thank the lab of Dr. Pier Lorenzo Puri for myc-EZH2 and T367A-EZH2 vectors. This work was supported by the National institutes of Health (NIH) grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), R25GM086262 (PREP program, C.A.-G.), R01GM094231 (A.I.N.), T32CA140044 (J.R.), the University of Michigan Rogel Cancer Center support grant P30CA046592, the Karlene Kulp Fund Judy & Ken Robinson Fund (C.G.K.) and the Department of Defense award W81XWH-15-1-0019 (C.G.K. and Z.N.-C.).

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-05078-8

Cite this

Anwar, T., Arellano-Garcia, C., Ropa, J., Chen, Y. C., Kim, H. S., Yoon, E., Grigsby, S., Basrur, V., Nesvizhskii, A. I., Muntean, A., Gonzalez, M. E., Kidwell, K. M., Nikolovska-Coleska, Z., & Kleer, C. G. (2018). P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis. Nature communications, 9(1), [2801]. https://doi.org/10.1038/s41467-018-05078-8

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title = "P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis",

abstract = "Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.",

author = "Talha Anwar and Caroline Arellano-Garcia and James Ropa and Chen, {Yu Chih} and Kim, {Hong Sun} and Euisik Yoon and Sierrah Grigsby and Venkatesha Basrur and Nesvizhskii, {Alexey I.} and Andrew Muntean and Gonzalez, {Maria E.} and Kidwell, {Kelley M.} and Zaneta Nikolovska-Coleska and Kleer, {Celina G.}",

note = "Funding Information: We thank members of the Kleer lab for discussions during the execution of this project. We thank the lab of Dr. Pier Lorenzo Puri for myc-EZH2 and T367A-EZH2 vectors. This work was supported by the National institutes of Health (NIH) grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), R25GM086262 (PREP program, C.A.-G.), R01GM094231 (A.I.N.), T32CA140044 (J.R.), the University of Michigan Rogel Cancer Center support grant P30CA046592, the Karlene Kulp Fund Judy & Ken Robinson Fund (C.G.K.) and the Department of Defense award W81XWH-15-1-0019 (C.G.K. and Z.N.-C.). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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Anwar, T, Arellano-Garcia, C, Ropa, J, Chen, YC, Kim, HS, Yoon, E, Grigsby, S, Basrur, V, Nesvizhskii, AI, Muntean, A, Gonzalez, ME, Kidwell, KM, Nikolovska-Coleska, Z & Kleer, CG 2018, 'P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis', Nature communications, vol. 9, no. 1, 2801. https://doi.org/10.1038/s41467-018-05078-8

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T1 - P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis

AU - Anwar, Talha

AU - Arellano-Garcia, Caroline

AU - Ropa, James

AU - Chen, Yu Chih

AU - Kim, Hong Sun

AU - Yoon, Euisik

AU - Grigsby, Sierrah

AU - Basrur, Venkatesha

AU - Nesvizhskii, Alexey I.

AU - Muntean, Andrew

AU - Gonzalez, Maria E.

AU - Kidwell, Kelley M.

AU - Nikolovska-Coleska, Zaneta

AU - Kleer, Celina G.

N1 - Funding Information: We thank members of the Kleer lab for discussions during the execution of this project. We thank the lab of Dr. Pier Lorenzo Puri for myc-EZH2 and T367A-EZH2 vectors. This work was supported by the National institutes of Health (NIH) grants R01CA125577 and R01CA107469 (C.G.K.), F30CA19084 (T.A.), R25GM086262 (PREP program, C.A.-G.), R01GM094231 (A.I.N.), T32CA140044 (J.R.), the University of Michigan Rogel Cancer Center support grant P30CA046592, the Karlene Kulp Fund Judy & Ken Robinson Fund (C.G.K.) and the Department of Defense award W81XWH-15-1-0019 (C.G.K. and Z.N.-C.). Publisher Copyright: © 2018 The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.

AB - Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function.

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P38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis

Abstract

Bibliographical note

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