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

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

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.

Highlights

The Hippo pathway is a central cellular pathway, which regulates homeostasis and plays prominent roles in carcinogenesis and regenerative processes
The expression of the Hippo cofactor Yes-associated protein 1 (YAP1) was investigated by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) sections from normal parathyroid glands (PaNs, n = 4), parathyroid adenomas (PAds, n = 11), and parathyroid carcinomas (PCas, n = 6) (Figure 1)
Nuclear YAP1 accumulation was evident in a substantial proportion of parathyroid epithelial cells in normal parathyroid glands and parathyroid adenomas, while the accumulation of YAP1 in the cytosol was variably reduced in cells of parathyroid adenomas, which sometimes showed a more intense nuclear staining compared with cells in normal glands

Summary

Introduction

The Hippo pathway is a central cellular pathway, which regulates homeostasis and plays prominent roles in carcinogenesis and regenerative processes. YAP1 (Yes-associated protein 1) and its paralog transcriptional coactivator with PDZ-binding motif, Tafazzin (TAZ), which are the principal effectors of the Hippo signaling pathway, are relatively inactive in adults to maintain organ homeostasis, while they are robustly induced during neoplastic disorders [1,2,3]. The Hippo tumor suppressor pathway functions to inhibit the activity of YAP/TAZ transcriptional coactivators. The Hippo pathway is complex and involves the MST1 and MST2 (Mammalian STE20-like protein kinase 1/2), LATS1 and LATS2 2), and adaptor proteins SAV1 (Salvador homolog 1) and MOB kinase activator 1A and Parathyroid tumors, which are mainly benign, are the second most frequent endocrine neoplasia clinically associated with the endocrine disorder known as primary hyperparathyroidism, which represents a frequently occurring cause of osteoporosis and bone fragility.

Methods

Results

Discussion

Conclusion