Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors

Int J Mol Sci. 2021 Feb 18;22(4):2016. doi: 10.3390/ijms22042016.

Abstract

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated 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.

Keywords: CASR; LATS1/2; MEN1; YAP1; parathormone; parathyroid tumors.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amides / pharmacology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Gene Expression / drug effects
  • HEK293 Cells
  • Humans
  • Parathyroid Glands / metabolism*
  • Parathyroid Neoplasms / genetics*
  • Parathyroid Neoplasms / metabolism
  • Phenethylamines / pharmacology
  • Propylamines / pharmacology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Pyridines / pharmacology
  • RNA Interference
  • Receptors, Calcium-Sensing / agonists
  • Receptors, Calcium-Sensing / genetics*
  • Receptors, Calcium-Sensing / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • YAP-Signaling Proteins
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
  • Adaptor Proteins, Signal Transducing
  • Amides
  • MEN1 protein, human
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • Phenethylamines
  • Propylamines
  • Proto-Oncogene Proteins
  • Pyridines
  • Receptors, Calcium-Sensing
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Y 27632
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • LATS1 protein, human
  • LATS2 protein, human
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases