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Published on: March 14, 2017
Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors
Giulia Stefania Tavanti1,2, Chiara Verdelli1, Annamaria Morotti3
1Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, 20161 Milan, Italy.
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.
Insights
The Hippo pathway, including YAP1 and LATS1/2, is implicated in parathyroid tumors. Reduced YAP1/LATS1/2 and a novel CASR-ROCK-YAP1 axis suggest a tumor suppressor role for these proteins.
Area of Science:
- Oncology
- Cell Biology
- Endocrinology
Background:
- The Hippo pathway regulates organ size and is implicated in tumorigenesis.
- Yes-associated protein 1 (YAP1) is a key coactivator in the Hippo pathway.
- Parathyroid tumors, such as adenomas and carcinomas, are often linked to primary hyperparathyroidism.
Purpose of the Study:
- To investigate the role of the Hippo pathway, specifically YAP1 and LATS1/2, in parathyroid tumors.
- To explore the relationship between YAP1, LATS1/2, and the multiple endocrine neoplasia type 1 (MEN1) oncosuppressor.
- To examine the influence of the calcium-sensing receptor (CASR) on YAP1 activity in parathyroid cells.
Main Methods:
- Analysis of YAP1 and LATS1/2 expression in normal parathyroid glands versus parathyroid adenomas (PAds) and carcinomas.
- Gene silencing experiments to study the interplay between YAP1 and MEN1.
- Treatment of patient-derived PAd cells and HEK293A cells with a CASR agonist (R568) and ROCK inhibitors (Y27632, H1152).
- Assessment of YAP1 target gene expression (CYR61, CTGF, WNT5A) following CASR activation.
Main Results:
- Reduced nuclear YAP1 and LATS1/2 expression were observed in parathyroid tumors compared to normal glands.
- YAP1 silencing decreased MEN1 expression, while MEN1 silencing increased YAP1 expression.
- CASR activation led to YAP1 nuclear accumulation, mediated by the ROCK pathway.
- CASR activation upregulated YAP1 target genes, an effect dependent on YAP1 presence.
Conclusions:
- Preliminary evidence suggests the Hippo pathway is involved in human parathyroid tumors.
- A novel CASR-ROCK-YAP1 signaling axis exists in parathyroid cells.
- YAP1 and LATS1/2 may function as tumor suppressors in parathyroid tumorigenesis.
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