Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP

Abstract

The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAPinduced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.

Lats2 is critical for the pluripotency and proper differentiation of stem cells

“…34 As expected, VP strongly decreased CTGF expression in both WT and Lats2 À / À ESCs (Figure 7b). Importantly, VP did not rescue the differentiation defect of Lats2 À / À ESCs, as assessed by its effect on Oct4 expression (Figure 7c).…”

A temporal requirement for Hippo signaling in mammary gland differentiation, growth, and tumorigenesis

“…For this purpose, we took advantage of verteporfin (VP), a recently reported YAP inhibitor that interferes with the physical association between YAP and its obligatory DNA-binding transcription factor partner, TEAD/TEF (Liu-Chittenden et al 2012). A collection of eight commonly used human breast cancer lines with varying levels of YAP expression (Supplemental Fig.…”

Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

“…YAP has no transcriptional activity and its actions are dependent on downstream transcriptional factors. Recent drug library screening identified a small molecule verteporfin, capable of inhibiting YAP association with TEAD transcriptional factors and suppressing YAP-induced liver overgrowth (11). Because fragmentation-induced CCN and BIRC changes were transient, we injected day 10 mice for 3 h with verteporfin before obtaining ovaries for fragmentation.…”

“…Ovarian fragmentation increased actin polymerization, decreased phospho-YAP (pYAP) levels, increased nuclear localization of YAP, as well as enhanced expression of CCN growth factors and BIRC apoptosis inhibitors. Fragmentation-induced follicle growth was partially blocked by CCN2 antibodies and verteporfin, a small molecule that inhibits interactions of YAP with TEAD transcriptional factors (11).…”