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A comprehensive enhancer screen identifies TRAM2 as a key mediator of YAP oncogenesis

ABSTRACT: Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated-YAP associates with enhancer loci via TEAD4-DNA-binding protein, and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites were annotated, their functional importance is unknow. Here, we implemented a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrated its robustness, and used it to reveal a network of enhancers required for YAP-mediated proliferation. We focused on Enhancer TRAM2, as its target gene TRAM2 showed the strongest expression-correlation with YAP in nearly all tumor types. Interestingly, TRAM2 phenocopied YAP-induced cell proliferation, migration and invasion phenotypes, and correlated with poor patient survival. Mechanistically, we identified FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness.

INSTRUMENT(S): Q Exactive HF-X, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Mammary Gland Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Onno Bleijerveld

LAB HEAD: Maarten Altelaar

PROVIDER: PXD018559 | Pride | 2021-01-14

REPOSITORIES: Pride

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			Action	DRS
	20190604_HFX_Li_MCF10A_proteome.msf	Msf
	20190604_HFX_Li_proteome_MCF10A_EMPTY_OE_rep1.raw	Raw
	20190604_HFX_Li_proteome_MCF10A_EMPTY_OE_rep2.raw	Raw
	20190604_HFX_Li_proteome_MCF10A_EMPTY_OE_rep3.raw	Raw
	20190604_HFX_Li_proteome_MCF10A_TRAM2_PURO_OE_rep1.raw	Raw

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A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

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