An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis

Harvey W. Smith; Alison Hirukawa; Virginie Sanguin-Gendreau; Ipshita Nandi; Catherine R. Dufour; Dongmei Zuo; Kristofferson Tandoc; Matthew Leibovitch; Salendra Singh; Jonathan P. Rennhack; Matthew Swiatnicki; Cynthia Lavoie; Vasilios Papavasiliou; Carolin Temps; Neil O. Carragher; Asier Unciti-Broceta; Paul Savage; Mark Basik; Vincent van Hoef; Ola Larsson; Caroline L. Cooper; Ana Cristina Vargas Calderon; Jane Beith; Ewan Millar; Christina Selinger; Vincent Giguère; Morag Park; Lyndsay N. Harris; Vinay Varadan; Eran R. Andrechek; Sandra A. O’Toole; Ivan Topisirovic; William J. Muller

doi:10.1038/s41467-019-10681-4

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis

Harvey W. Smith, Alison Hirukawa, Virginie Sanguin-Gendreau, Ipshita Nandi, Catherine R. Dufour, Dongmei Zuo, Kristofferson Tandoc, Matthew Leibovitch, Salendra Singh, Jonathan P. Rennhack, Matthew Swiatnicki, Cynthia Lavoie, Vasilios Papavasiliou, Carolin Temps, Neil O. Carragher, Asier Unciti-Broceta, Paul Savage, Mark Basik, Vincent van Hoef, Ola LarssonCaroline L. Cooper, Ana Cristina Vargas Calderon, Jane Beith, Ewan Millar, Christina Selinger, Vincent Giguère, Morag Park, Lyndsay N. Harris, Vinay Varadan, Eran R. Andrechek, Sandra A. O’Toole, Ivan Topisirovic, William J. Muller

Western Sydney University

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

25 Citations (Scopus)

Abstract

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.

Original language	English
Article number	2901
Number of pages	19
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-10681-4
Publication status	Published - 2019

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Keywords

bioenergetics
breast
cancer
carcinogenesis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-10681-4

Cite this

Smith, H. W., Hirukawa, A., Sanguin-Gendreau, V., Nandi, I., Dufour, C. R., Zuo, D., Tandoc, K., Leibovitch, M., Singh, S., Rennhack, J. P., Swiatnicki, M., Lavoie, C., Papavasiliou, V., Temps, C., Carragher, N. O., Unciti-Broceta, A., Savage, P., Basik, M., van Hoef, V., ... Muller, W. J. (2019). An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis. Nature Communications, 10, Article 2901. https://doi.org/10.1038/s41467-019-10681-4

@article{df5303ccaadc438d80eb6b250bfbbd52,

title = "An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis",

abstract = "Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.",

keywords = "bioenergetics, breast, cancer, carcinogenesis",

author = "Smith, {Harvey W.} and Alison Hirukawa and Virginie Sanguin-Gendreau and Ipshita Nandi and Dufour, {Catherine R.} and Dongmei Zuo and Kristofferson Tandoc and Matthew Leibovitch and Salendra Singh and Rennhack, {Jonathan P.} and Matthew Swiatnicki and Cynthia Lavoie and Vasilios Papavasiliou and Carolin Temps and Carragher, {Neil O.} and Asier Unciti-Broceta and Paul Savage and Mark Basik and {van Hoef}, Vincent and Ola Larsson and Cooper, {Caroline L.} and {Vargas Calderon}, {Ana Cristina} and Jane Beith and Ewan Millar and Christina Selinger and Vincent Gigu{\`e}re and Morag Park and Harris, {Lyndsay N.} and Vinay Varadan and Andrechek, {Eran R.} and O{\textquoteright}Toole, {Sandra A.} and Ivan Topisirovic and Muller, {William J.}",

year = "2019",

doi = "10.1038/s41467-019-10681-4",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

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Smith, HW, Hirukawa, A, Sanguin-Gendreau, V, Nandi, I, Dufour, CR, Zuo, D, Tandoc, K, Leibovitch, M, Singh, S, Rennhack, JP, Swiatnicki, M, Lavoie, C, Papavasiliou, V, Temps, C, Carragher, NO, Unciti-Broceta, A, Savage, P, Basik, M, van Hoef, V, Larsson, O, Cooper, CL, Vargas Calderon, AC, Beith, J, Millar, E, Selinger, C, Giguère, V, Park, M, Harris, LN, Varadan, V, Andrechek, ER, O’Toole, SA, Topisirovic, I & Muller, WJ 2019, 'An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis', Nature Communications, vol. 10, 2901. https://doi.org/10.1038/s41467-019-10681-4

TY - JOUR

T1 - An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis

AU - Smith, Harvey W.

AU - Hirukawa, Alison

AU - Sanguin-Gendreau, Virginie

AU - Nandi, Ipshita

AU - Dufour, Catherine R.

AU - Zuo, Dongmei

AU - Tandoc, Kristofferson

AU - Leibovitch, Matthew

AU - Singh, Salendra

AU - Rennhack, Jonathan P.

AU - Swiatnicki, Matthew

AU - Lavoie, Cynthia

AU - Papavasiliou, Vasilios

AU - Temps, Carolin

AU - Carragher, Neil O.

AU - Unciti-Broceta, Asier

AU - Savage, Paul

AU - Basik, Mark

AU - van Hoef, Vincent

AU - Larsson, Ola

AU - Cooper, Caroline L.

AU - Vargas Calderon, Ana Cristina

AU - Beith, Jane

AU - Millar, Ewan

AU - Selinger, Christina

AU - Giguère, Vincent

AU - Park, Morag

AU - Harris, Lyndsay N.

AU - Varadan, Vinay

AU - Andrechek, Eran R.

AU - O’Toole, Sandra A.

AU - Topisirovic, Ivan

AU - Muller, William J.

PY - 2019

Y1 - 2019

N2 - Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.

AB - Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.

KW - bioenergetics

KW - breast

KW - cancer

KW - carcinogenesis

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:52361

U2 - 10.1038/s41467-019-10681-4

DO - 10.1038/s41467-019-10681-4

M3 - Article

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 2901

ER -

An ErbB2/c-Src axis links bioenergetics with PRC2 translation to drive epigenetic reprogramming and mammary tumorigenesis

Abstract

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