Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

• Published in: Cell reports (Cambridge) Vol. 21; no. 2; pp. 495 - 507
• Main Authors: Shah, Sagar R., David, Justin M., Tippens, Nathaniel D., Mohyeldin, Ahmed, Martinez-Gutierrez, Juan C., Ganaha, Sara, Schiapparelli, Paula, Hamilton, Duane H., Palena, Claudia, Levchenko, Andre, Quiñones-Hinojosa, Alfredo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-10-2017; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; brachyury; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma - genetics; Carcinoma - metabolism; Cell Line, Tumor; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - metabolism; Chondroma - genetics; Chondroma - metabolism; Chondroma - pathology; chordoma; Fetal Proteins - genetics; Fetal Proteins - metabolism; Gene Expression Regulation, Neoplastic; glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; growth; Humans; lung carcinoma; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mice; Neoplastic Stem Cells - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; stremness; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Transcription Factors; YAP; glioblastoma; lung carcinoma; YAP; stremness; growth; chordoma; brachyury
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.09.057

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.
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•Chordomas harbor a putative cancer stem cell population that is driven by brachyury•Brachyury-YAP regulatory axis: identification of a direct transcriptional regulator of YAP•Brachyury can enhance YAP activity through a post-transcriptional mechanism in carcinomas•Brachyury-YAP activity is tied to tumor aggressiveness in several types of cancers
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.