# YAP and TEAD Are Transcriptional Regulators of Neuroendocrine Differentiation and Growth in Carcinoid Cells

## TL;DR

Low YAP levels in carcinoid tumors allow neuroendocrine cell growth by preventing YAP-TEAD interactions that otherwise suppress these features.

## Contribution

Identifies YAP-TEAD as regulators of neuroendocrine differentiation and growth in carcinoid cells.

## Key findings

- Active YAP inhibits neuroendocrine markers and cell proliferation in carcinoid cells.
- TEAD-binding defective YAP recovers neuroendocrine features and growth.
- YAP-TEAD binding alters gene expression of TGF-β and Notch pathways.

## Abstract

Molecular regulators of variably aggressive carcinoid tumors are unknown. Since carcinoids have low expression of Yes-associated protein (YAP), it was hypothesized that low YAP expression provides a molecular advantage to carcinoids by preventing YAP from binding its partner, TEA domain transcription factor (TEAD). To test this hypothesis, constitutively active YAP and a TEAD-binding defective form of YAP were overexpressed in lung (H727) and pancreatic (BON1) carcinoid cells. It was found that active YAP overexpression inhibited neuroendocrine markers, morphology, cell proliferation, and anchorage-independent cell growth, whereas TEAD-binding defective YAP recovered these features. Through integrated chromatin immunoprecipitation and RNA sequencing analyses, it was found that YAP-TEAD binding down-regulated neuroendocrine transcription factor genes and up-regulated select transforming growth factor (TGF-β) superfamily and Notch genes related to cell growth. It was concluded that low YAP expression permits neuroendocrine differentiation and growth in carcinoid cells by preventing YAP-TEAD binding and subsequent dysregulation of gene targets. These results identify unknown molecular mechanisms in carcinoid development that may apply to the broader family of neuroendocrine cancers.