Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

Stephin J Vervoort*; Olivier G de Jong*; M Guy Roukens*; Cynthia L Frederiks*; Jeroen F Vermeulen; Ana Rita Lourenço; Laura Bella; Ana Tufegdzic Vidakovic; José L Sandoval; Cathy Moelans; Miranda van Amersfoort; Margaret J Dallman; Alejandra Bruna; Carlos Caldas; Edward Nieuwenhuis; Elsken van der Wall; Patrick Derksen; Paul van Diest; Marianne C Verhaar; Eric W-F Lam; Michal Mokry; Paul J Coffer

doi:10.7554/eLife.27706

Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

Stephin J Vervoort*, Olivier G de Jong*, M Guy Roukens*, Cynthia L Frederiks*, Jeroen F Vermeulen, Ana Rita Lourenço, Laura Bella, Ana Tufegdzic Vidakovic, José L Sandoval, Cathy Moelans, Miranda van Amersfoort, Margaret J Dallman, Alejandra Bruna, Carlos Caldas, Edward Nieuwenhuis, Elsken van der Wall, Patrick Derksen, Paul van Diest, Marianne C Verhaar, Eric W-F LamMichal Mokry, Paul J Coffer

Science

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

Abstract

The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

Original language	English
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.27706
Publication status	Published - 3 Dec 2018

Bibliographical note

Keywords

Animals
Breast Neoplasms/blood supply
Chromatin/metabolism
Culture Media, Conditioned/pharmacology
Endothelin-1/metabolism
Epigenesis, Genetic
Epithelial Cells/drug effects
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic/drug effects
Gene Regulatory Networks
HEK293 Cells
Humans
Neoplasm Metastasis
Neovascularization, Pathologic/genetics
Promoter Regions, Genetic/genetics
RNA, Messenger/genetics
SOXC Transcription Factors/genetics
Survival Analysis
Trans-Activators/metabolism
Transcription, Genetic
Xenograft Model Antitumor Assays
Zebrafish

UN SDGs

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

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10.7554/eLife.27706Licence: CC BY

Cite this

Vervoort*, S. J., de Jong*, O. G., Roukens*, M. G., Frederiks*, C. L., Vermeulen, J. F., Lourenço, A. R., Bella, L., Vidakovic, A. T., Sandoval, J. L., Moelans, C., van Amersfoort, M., Dallman, M. J., Bruna, A., Caldas, C., Nieuwenhuis, E., van der Wall, E., Derksen, P., van Diest, P., Verhaar, M. C., ... Coffer, P. J. (2018). Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis. eLife, 7. https://doi.org/10.7554/eLife.27706

@article{2aac3cac87f4438ca9a5a4a4cbd22e3e,

title = "Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis",

abstract = "The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.",

keywords = "Animals, Breast Neoplasms/blood supply, Chromatin/metabolism, Culture Media, Conditioned/pharmacology, Endothelin-1/metabolism, Epigenesis, Genetic, Epithelial Cells/drug effects, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic/drug effects, Gene Regulatory Networks, HEK293 Cells, Humans, Neoplasm Metastasis, Neovascularization, Pathologic/genetics, Promoter Regions, Genetic/genetics, RNA, Messenger/genetics, SOXC Transcription Factors/genetics, Survival Analysis, Trans-Activators/metabolism, Transcription, Genetic, Xenograft Model Antitumor Assays, Zebrafish",

author = "Vervoort*, {Stephin J} and {de Jong*}, {Olivier G} and Roukens*, {M Guy} and Frederiks*, {Cynthia L} and Vermeulen, {Jeroen F} and Louren{\c c}o, {Ana Rita} and Laura Bella and Vidakovic, {Ana Tufegdzic} and Sandoval, {Jos{\'e} L} and Cathy Moelans and {van Amersfoort}, Miranda and Dallman, {Margaret J} and Alejandra Bruna and Carlos Caldas and Edward Nieuwenhuis and {van der Wall}, Elsken and Patrick Derksen and {van Diest}, Paul and Verhaar, {Marianne C} and Lam, {Eric W-F} and Michal Mokry and Coffer, {Paul J}",

note = "{\textcopyright} 2018, Vervoort et al.",

year = "2018",

month = dec,

day = "3",

doi = "10.7554/eLife.27706",

language = "English",

volume = "7",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

Vervoort*, SJ, de Jong*, OG, Roukens*, MG, Frederiks*, CL, Vermeulen, JF, Lourenço, AR, Bella, L, Vidakovic, AT, Sandoval, JL, Moelans, C, van Amersfoort, M, Dallman, MJ, Bruna, A, Caldas, C, Nieuwenhuis, E, van der Wall, E, Derksen, P, van Diest, P, Verhaar, MC, Lam, EW-F, Mokry, M & Coffer, PJ 2018, 'Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis', eLife, vol. 7. https://doi.org/10.7554/eLife.27706

TY - JOUR

T1 - Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

AU - Vervoort, Stephin J

AU - de Jong, Olivier G

AU - Roukens, M Guy

AU - Frederiks, Cynthia L

AU - Vermeulen, Jeroen F

AU - Lourenço, Ana Rita

AU - Bella, Laura

AU - Vidakovic, Ana Tufegdzic

AU - Sandoval, José L

AU - Moelans, Cathy

AU - van Amersfoort, Miranda

AU - Dallman, Margaret J

AU - Bruna, Alejandra

AU - Caldas, Carlos

AU - Nieuwenhuis, Edward

AU - van der Wall, Elsken

AU - Derksen, Patrick

AU - van Diest, Paul

AU - Verhaar, Marianne C

AU - Lam, Eric W-F

AU - Mokry, Michal

AU - Coffer, Paul J

PY - 2018/12/3

Y1 - 2018/12/3

N2 - The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

AB - The expression of the transcription factor SOX4 is increased in many human cancers, however, the pro-oncogenic capacity of SOX4 can vary greatly depending on the type of tumor. Both the contextual nature and the mechanisms underlying the pro-oncogenic SOX4 response remain unexplored. Here, we demonstrate that in mammary tumorigenesis, the SOX4 transcriptional network is dictated by the epigenome and is enriched for pro-angiogenic processes. We show that SOX4 directly regulates endothelin-1 (ET-1) expression and can thereby promote tumor-induced angiogenesis both in vitro and in vivo. Furthermore, in breast tumors, SOX4 expression correlates with blood vessel density and size, and predicts poor-prognosis in patients with breast cancer. Our data provide novel mechanistic insights into context-dependent SOX4 target gene selection, and uncover a novel pro-oncogenic role for this transcription factor in promoting tumor-induced angiogenesis. These findings establish a key role for SOX4 in promoting metastasis through exploiting diverse pro-tumorigenic pathways.

KW - Animals

KW - Breast Neoplasms/blood supply

KW - Chromatin/metabolism

KW - Culture Media, Conditioned/pharmacology

KW - Endothelin-1/metabolism

KW - Epigenesis, Genetic

KW - Epithelial Cells/drug effects

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Gene Regulatory Networks

KW - HEK293 Cells

KW - Humans

KW - Neoplasm Metastasis

KW - Neovascularization, Pathologic/genetics

KW - Promoter Regions, Genetic/genetics

KW - RNA, Messenger/genetics

KW - SOXC Transcription Factors/genetics

KW - Survival Analysis

KW - Trans-Activators/metabolism

KW - Transcription, Genetic

KW - Xenograft Model Antitumor Assays

KW - Zebrafish

U2 - 10.7554/eLife.27706

DO - 10.7554/eLife.27706

M3 - Article

C2 - 30507376

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

ER -

Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis

Abstract

Bibliographical note

Keywords

UN SDGs

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