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

Published: 01/12/2018


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.

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