Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer

Shenghong Ma, Tracy Tang, Gary Probst, Andrei Konradi, Chunyu Jin, Fulong Li, J. Silvio Gutkind, Xiang-Dong Fu and Kun-Liang Guan ()
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Shenghong Ma: University of California San Diego
Tracy Tang: Vivace Therapeutics
Gary Probst: Vivace Therapeutics
Andrei Konradi: Vivace Therapeutics
Chunyu Jin: University of California San Diego
Fulong Li: University of California San Diego
J. Silvio Gutkind: University of California San Diego
Xiang-Dong Fu: University of California San Diego
Kun-Liang Guan: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER+ breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER+ breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.

Date: 2022
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DOI: 10.1038/s41467-022-28691-0

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