Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Sagar R. Shah, Justin M. David, Nathaniel D. Tippens, Ahmed Mohyeldin, Juan C. Martinez-Gutierrez, Sara Ganaha, Paula Schiapparelli, Duane H. Hamilton, Claudia Palena, Andre Levchenko, Alfredo Quiñones-Hinojosa

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors. Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers.

Original languageEnglish (US)
Pages (from-to)495-507
Number of pages13
JournalCell reports
Volume21
Issue number2
DOIs
StatePublished - Oct 10 2017

Keywords

  • YAP
  • brachyury
  • chordoma
  • glioblastoma
  • growth
  • lung carcinoma
  • stremness

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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