Yes-Associated Protein Contributes to the Development of Human Cutaneous Squamous Cell Carcinoma via Activation of RAS

Abstract

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin malignant tumors with an increasing incidence. Studies have shown that Yes-associated protein (YAP) participates in the development of a variety of tumors as an oncogene, but to our knowledge its role in cSCC has not been reported. In this study, we used immunohistochemistry to show that YAP expression was elevated in cSCC samples of different stages versus in normal skin and that it was well correlated with the progression of the disease. Down-regulation of YAP in cSCC cell lines A431 and SCL-1 inhibited cell proliferation by inducing growth arrest during the G1/S phase transition, promoted apoptosis, and reduced invasion and migration abilities in vitro. Conversely, overexpression of YAP promoted cell proliferation and protected cells against basal and chemotherapy-induced apoptosis. These oncogenic effects of YAP were associated with activation of the RAS protein and its downstream AKT and ERK. Using a mouse xenograft model, we further showed that YAP depletion inhibited cSCC tumor growth in vivo. Our results suggested that YAP is involved in the carcinogenesis and development of cSCC and that it may serve as a biomarker or therapeutic target of this disease.

ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis

“…Furthermore, we found that YAP, like ACTL6A and p63, was required to sustain oncosphere formation by HNSCC cells (Figure 6E). In keeping with these data, a recent report demonstrates that activated YAP is required for in vivo tumorigenesis in cutaneous squamous cell carcinoma (Jia et al, 2016). Collectively, these data reveal that ACTL6A/p63 are required to induce and sustain YAP localization and activity in HNSCC.…”

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

“…It is well documented that YAP and TAZ are required for normal epidermal development and hair growth in the mouse304142, and YAP and TAZ drive pro-tumorigenic signals in mouse and human cSCC3043. Nevertheless, there is ambiguity about YAP/TAZ function: YAP and TAZ are largely dispensible for homoeostasis of the IFE in adult mouse skin3042, and in cSCC both growth-promoting and growth-inhibiting functions have been documented4344.…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…In the skin, YAP is required for epidermal barrier formation, hair follicle development, and maintenance of the epidermal stem cell compartment (Zhang et al 2011;Barry and Camargo 2013;O'Neill 2015). Overexpression of YAP in transgenic mice promotes squamous cell carcinoma formation (Chan et al 2011;Jia et al 2016), whereas its knockdown inhibits cutaneous wound healing (Lee et al 2014), suggesting a central role in regulating proliferation. YAP and TAZ also respond to the rigidity of the extracellular matrix, cell geometry, cell density, cell polarity, and the status of the actin cytoskeleton.…”