Overexpression of YAP1 induces immortalization of normal human keratinocytes by blocking clonal evolution

Abstract

YAP1 is a transcriptional co-activator able to bind several transcription factors. YAP1 was termed a candidate oncogene after it was shown to be in human chromosome 11q22 amplicon; besides the genomic amplification, several experiments indicated that it has oncogenic function. However, YAP1 was also reported to be a tumor suppressor as its gene locus is deleted in some breast cancers. To clarify the role of this protein in the physiology of rapidly renewal cells, we investigated YAP1 in human keratinocytes. Here, we show that YAP1 overexpression in primary human keratinocytes blocks clonal evolution and induces cell immortalization, but not malignant transformation. YAP1 overexpression led to an increase in cell proliferation, colony forming efficiency and holoclone percentage. Cells escaped from senescence, immortalized but still remained unable to grow in soft agar or express mesenchymal markers, suggesting that YAP1 overexpression is not sufficient to promote a complete epithelial-mesenchymal transition and tumorigenic transformation. Protein analysis showed an increase in epithelial proliferation markers and a decrease in epithelial differentiation markers. The expression of LEKTI, a late differentiation marker, dramatically dropped to undetectable levels. Taken together, these data suggest that YAP1-overexpressing keratinocytes are maintained in the proliferative compartment.

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

“…D’Addario et al . 35 found that overexpression of YAP in normal human primary keratinocytes interfered with their normal differentiation process and led to immortalized proliferation, upregulation of the epithelial proliferation markers p63 and PCNA, and downregulation of the differentiation markers 14-3-3σ and LEKTI. In HaCaT cells, an immortalized epidermal keratinocyte cell line widely used as a cell model of psoriasis 15 – 18 , we found a high level of YAP that almost reached the level of YAP in the cSCC cell line A431 and was significantly higher than that in primary keratinocytes.…”

miR‐483‐3p controls proliferation in wounded epithelial cells

“…Phosphorylation of YAP1 mediated by the LATS (large tumor suppressor) kinase, a downstream effector of the Hippo pathway, inhibits the YAP1 transcriptional activity through cytosolic sequestration and is involved in cell contact inhibition. Furthermore, recent reports demonstrate the crucial function of YAP1 in the control of epidermal proliferation (47, 48). Interestingly, our results clearly establish down‐regulation of YAP1 by miR‐483‐3p as a new regulatory mechanism.…”

A prospect of cell immortalization combined with matrix microenvironmental optimization strategy for tissue engineering and regeneration

“…Yes-associated protein 1 (YAP), a major downstream effector of the Hippo pathway, is phosphorylated and inactivated by the serine/threonine kinases large tumor suppressor 1 (LATS1) and LATS2 [102, 103]. YAP dephosphorylation is associated with the senescence of rat nucleus pulposus cells and overexpression of YAP in primary human keratinocytes blocks clonal evolution and induces cell immortalization [104, 105]. Coordination of the Hippo pathway and p53 occurs in response to various types of stress signals including replication and oncogenic Ras.…”