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

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.