Yes-associated protein 1 is a novel calcium sensing receptor target in human parathyroid tumors

Giulia Stefania Tavanti, Chiara Verdelli, Annamaria Morotti, Paola Maroni, Vito Guarnieri, Alfredo Scillitani, Rosamaria Silipigni, Silvana Guerneri, Riccardo Maggiore, Gilberto Mari, Leonardo Vicentini, Paolo Dalino Ciaramella, Valentina Vaira, Sabrina Corbetta

Research output: Contribution to journalArticlepeer-review

Abstract

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we inves-tigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1 (MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

Original languageEnglish
Article number2016
Pages (from-to)1-19
Number of pages19
JournalInternational Journal of Molecular Sciences
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2 2021

Keywords

  • CASR
  • LATS1/2
  • MEN1
  • Parathormone
  • Parathyroid tumors
  • YAP1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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