Pro-Invasive Activity of the Hippo Pathway Effectors YAP and TAZ in Cutaneous Melanoma

Abstract

YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial–mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain–dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.

Expression of YAP in the Skin Lesions of Lichen Planus

“…By immunohistochemical staining, researchers have found that YAP is upregulated in a wide variety of human cancers including liver cancer [25], breast cancer [26], lung cancer [27], gastric cancer, esophageal cancer [28] and colorectal cancer [29]. YAP was also found to be correlated with some skin and mucosa tumors, such as oral squamous cell carcinoma [30], malignant melanoma [31,32] and head and neck cancers [33]. But so far, little is known about expression of YAP in LP.…”

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

“…3). This is of relevance to therapy because increased expression of TAZ was reported in various cancers, including breast (42), colon (43), non-small cell lung cancer (44), and melanoma (45), making it a bona fide oncogene. TAZ is also believed to endow tumor cells with cancer stem cell properties (42) and cooperate with both b-catenin and Smads downstream of Wnt and TGF-b, respectively, to induce expression of pro-EMT genes (46).…”

Cell Density Regulates Cancer Metastasis Via the Hippo Pathway

“…The Hippo pathway has been linked to several aspect of metastasis. Lamar et al have shown that YAP interaction with the TEAD/TEF family of transcription factors strongly enhances metastasis in breast cancer and melanoma cells [21][22][23]. Another study suggests a proinvasive role for both Hippo pathway effectors YAP and TAZ in cutaneous melanoma [28].…”

“…Lamar et al have shown that YAP interaction with the TEAD/TEF family of transcription factors strongly enhances metastasis in breast cancer and melanoma cells [21][22][23]. Another study suggests a proinvasive role for both Hippo pathway effectors YAP and TAZ in cutaneous melanoma [28]. In lung cancer, knockdown of YAP and TAZ reduced cell migration and transplantation of metastatic disease in vivo [21,23].…”

“…Also, YAP expression or activation has been shown to correlate with poor disease outcome [11,[19][20]. YAP transcriptional activity is also associated with metastasis of melanoma, lung and breast cancer [21][22][23]. In pancreatic cancer that is driven almost exclusively by mutant KRAS, the laboratory of Chunling Yi at Georgetown University showed that YAP is rate limiting for malignant progression irrespective of the presence of mutant P53 [24].…”