Yes-associated protein promotes the abnormal proliferation of psoriatic keratinocytes via an amphiregulin dependent pathway

Abstract

Psoriasis is a chronic inflammatory skin disease with high morbidity, poor treatment methods and high rates of relapse. Keratinocyte hyperproliferation and shortened cell cycles are important pathophysiological features of psoriasis. As a known oncogene, Yes-associated protein (YAP) plays a role in promoting cell proliferation and inhibiting cell apoptosis; however, whether YAP is involved in the pathogenesis of psoriasis remains to be determined. Amphiregulin (AREG), a transcriptional target of YAP, was found to be upregulated in psoriasis, and overexpression of AREG promoted keratinocyte proliferation. In the present study, immunohistochemistry showed that YAP expression was elevated in the skin of psoriasis patients and in the Imiquimod (IMQ) mouse model of psoriasis. Knockdown of YAP in HaCaT cells inhibited cell proliferation, caused cell cycle arrest in G0/G1 phase and promoted apoptosis. These changes in YAP-knockdown HaCaT cells were related to changes in AREG expression. We concluded that YAP may play an important role in the regulation of abnormal keratinocyte proliferation via an AREG-dependent pathway and that YAP could be a new target in the treatment of psoriasis.

Yes-Associated Protein Promotes the Development of Condyloma Acuminatum through EGFR Pathway Activation

“…CA is an epidermal disease, characterised by an excessive proliferation of keratinocytes, and therefore, we modulated YAP1 expression in keratinocytes in vitro, and showed that YAP1 promotes proliferation, migration, and inhibits the apoptosis of HaCaT cells, while the downregulation of YAP1 promotes apoptosis and inhibits the proliferation and migration of HaCaT cells. The downregulation of YAP1 in HaCaT cells was also shown in another study which revealed that YAP1 promotes the proliferation of psoriasis [12]. These findings agree with a previous report showing that YAP promotes proliferation and inhibits the apoptosis of cervical cancer cells, squamous cell carcinoma cells, lung cancer cells, and hepatoma cells [13].…”

RASSF1A Regulates the Abnormal Cell Proliferation in Psoriasis via Inhibition of YAP

“…After adding AREG to HaCaT cells following YAP knockdown, the original down-regulated proliferation rate was restored, but not to pre-knockdown levels. The study of related signaling pathways showed that the expression of key molecules in the STAT3, JAK2, NF-κB signaling pathway was down-regulated to varying degrees 6 . Since it was thought that low or loss of RASSF1A expression was mainly caused by hypermethylation of the CpG island in the promoter region 8 .…”

“…Research show that KC in psoriasis are apoptosis-resistant; it is, therefore, important to explore the causes of KC apoptosis imbalance and cell cycle acceleration when studying psoriasis pathogenesis 5 . In our previous study, we found that Yes-associated protein (YAP) was highly expressed in psoriatic lesions and was involved in its pathogenesis by regulating KC proliferation and apoptosis 6 . RAS-association domain family 1A (RASSF1A) is the most common negative regulator of RAS.…”

Caveolin as a Universal Target in Dermatology

“…Severe disturbances of this pathway were found in different hyperproliferative and inflammatory skin diseases as well as in neoplasia. Expression of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the major transcriptional mediators of the Hippo pathway, was reported to be significantly increased in clinical psoriatic specimens as well as in imiquimod-based mouse model of psoriasis [12]. Its expression was also strongly enhanced in the injured dermis two days after cutaneous wounding and these elevated levels were found in the whole wound area by day seven, whereas a knockdown of YAP/TAZ markedly reduces the expression of TGF-β and delayed wound closure [13].…”

“…Moreover, the lack of caveolae causes hyperactivation of YAP/TAZ. On the other hand, these Hippo mediators are involved in epithelial proliferation [17], and YAP promotes abnormal proliferation of psoriatic keratinocytes [12]. Cav-1 expression regulates YAP activity in response to changes in ECM stiffness [18].…”