Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Nishanth Belugali Nataraj; Ashish Noronha; Joo Sang Lee; Soma Ghosh; Harsha Raj Mohan Raju; Arunachalam Sekar; Binyamin Zuckerman; Moshit Lindzen; Emilio Tarcitano; Swati Srivastava; Michael Selitrennik; Ido Livneh; Diana Drago-Garcia; Oscar Rueda; Carlos Caldas; Sima Lev; Tamar Geiger; Aaron Ciechanover; Igor Ulitsky; Rony Seger; Eytan Ruppin; Yosef Yarden

doi:10.1016/j.celrep.2022.110418

Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Nishanth Belugali Nataraj, Ashish Noronha, Joo Sang Lee, Soma Ghosh, Harsha Raj Mohan Raju, Arunachalam Sekar, Binyamin Zuckerman, Moshit Lindzen, Emilio Tarcitano, Swati Srivastava, Michael Selitrennik, Ido Livneh, Diana Drago-Garcia, Oscar Rueda, Carlos Caldas, Sima Lev, Tamar Geiger, Aaron Ciechanover, Igor Ulitsky, Rony SegerEytan Ruppin, Yosef Yarden

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

16 Scopus citations

Abstract

By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.

Original language	English (US)
Article number	110418
Journal	Cell reports
Volume	38
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2022.110418
State	Published - Feb 22 2022
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs. Friedhelm Hildebrandt, Robert Weinberg, Jeffrey Wrana, Daniel Haber, Stefan Wiemann, and Tohru Itoh for plasmids and Dr. Raya Eilam-Altstadter for histology analyses. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies have been supported by the Israel Science Foundation ( ISF ), the Israel Cancer Research Fund ( ICRF ), the European Research Council ( ERC ), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation ( AMRF ).

Publisher Copyright:
© 2022

Keywords

breast cancer
cancer hallmark
EGF/ERK
importin
metastasis
nuclear pore
nuclear transport
TGF-β/SMAD
transcription factor
WNT/β-catenin

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

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

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10.1016/j.celrep.2022.110418

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Nataraj, N. B., Noronha, A., Lee, J. S., Ghosh, S., Mohan Raju, H. R., Sekar, A., Zuckerman, B., Lindzen, M., Tarcitano, E., Srivastava, S., Selitrennik, M., Livneh, I., Drago-Garcia, D., Rueda, O., Caldas, C., Lev, S., Geiger, T., Ciechanover, A., Ulitsky, I., ... Yarden, Y. (2022). Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors. Cell reports, 38(8), Article 110418. https://doi.org/10.1016/j.celrep.2022.110418

Nataraj, NB, Noronha, A, Lee, JS, Ghosh, S, Mohan Raju, HR, Sekar, A, Zuckerman, B, Lindzen, M, Tarcitano, E, Srivastava, S, Selitrennik, M, Livneh, I, Drago-Garcia, D, Rueda, O, Caldas, C, Lev, S, Geiger, T, Ciechanover, A, Ulitsky, I, Seger, R, Ruppin, E & Yarden, Y 2022, 'Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors', Cell reports, vol. 38, no. 8, 110418. https://doi.org/10.1016/j.celrep.2022.110418

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title = "Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors",

abstract = "By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.",

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author = "Nataraj, {Nishanth Belugali} and Ashish Noronha and Lee, {Joo Sang} and Soma Ghosh and {Mohan Raju}, {Harsha Raj} and Arunachalam Sekar and Binyamin Zuckerman and Moshit Lindzen and Emilio Tarcitano and Swati Srivastava and Michael Selitrennik and Ido Livneh and Diana Drago-Garcia and Oscar Rueda and Carlos Caldas and Sima Lev and Tamar Geiger and Aaron Ciechanover and Igor Ulitsky and Rony Seger and Eytan Ruppin and Yosef Yarden",

note = "Funding Information: We thank Drs. Friedhelm Hildebrandt, Robert Weinberg, Jeffrey Wrana, Daniel Haber, Stefan Wiemann, and Tohru Itoh for plasmids and Dr. Raya Eilam-Altstadter for histology analyses. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies have been supported by the Israel Science Foundation ( ISF ), the Israel Cancer Research Fund ( ICRF ), the European Research Council ( ERC ), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation ( AMRF ). Publisher Copyright: {\textcopyright} 2022",

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T2 - robust nucleocytoplasmic transport of transcription factors

AU - Nataraj, Nishanth Belugali

AU - Noronha, Ashish

AU - Lee, Joo Sang

AU - Ghosh, Soma

AU - Mohan Raju, Harsha Raj

AU - Sekar, Arunachalam

AU - Zuckerman, Binyamin

AU - Lindzen, Moshit

AU - Tarcitano, Emilio

AU - Srivastava, Swati

AU - Selitrennik, Michael

AU - Livneh, Ido

AU - Drago-Garcia, Diana

AU - Rueda, Oscar

AU - Caldas, Carlos

AU - Lev, Sima

AU - Geiger, Tamar

AU - Ciechanover, Aaron

AU - Ulitsky, Igor

AU - Seger, Rony

AU - Ruppin, Eytan

AU - Yarden, Yosef

N1 - Funding Information: We thank Drs. Friedhelm Hildebrandt, Robert Weinberg, Jeffrey Wrana, Daniel Haber, Stefan Wiemann, and Tohru Itoh for plasmids and Dr. Raya Eilam-Altstadter for histology analyses. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies have been supported by the Israel Science Foundation ( ISF ), the Israel Cancer Research Fund ( ICRF ), the European Research Council ( ERC ), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation ( AMRF ). Publisher Copyright: © 2022

PY - 2022/2/22

Y1 - 2022/2/22

N2 - By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.

AB - By establishing multi-omics pipelines, we uncover overexpression and gene copy-number alterations of nucleoporin-93 (NUP93), a nuclear pore component, in aggressive human mammary tumors. NUP93 overexpression enhances transendothelial migration and matrix invasion in vitro, along with tumor growth and metastasis in animal models. These findings are supported by analyses of two sets of naturally occurring mutations: rare oncogenic mutations and inactivating familial nephrotic syndrome mutations. Mechanistically, NUP93 binds with importins, boosts nuclear transport of importins' cargoes, such as β-catenin, and activates MYC. Likewise, NUP93 overexpression enhances the ultimate nuclear transport step shared by additional signaling pathways, including TGF-β/SMAD and EGF/ERK. The emerging addiction to nuclear transport exposes vulnerabilities of NUP93-overexpressing tumors. Congruently, myristoylated peptides corresponding to the nuclear translocation signals of SMAD and ERK can inhibit tumor growth and metastasis. Our study sheds light on an emerging hallmark of advanced tumors, which derive benefit from robust nucleocytoplasmic transport.

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KW - metastasis

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KW - transcription factor

KW - WNT/β-catenin

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Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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