Abstract
TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP.
Highlights
TAZ(WWTR1 is the gene) and YAP are transcriptional coactivators and paralogues of one another normally inhibited by the Hippo pathway, a developmentally important signal transduction pathway that limits tissue growth and organ size. [1, 2] The Hippo pathway is a series of core serine/threonine kinases including the STE20-like protein kinases 1 and 2 (MST1/2) [3,4,5,6] and the large tumor suppressor 1 and 2 (LATS1/2) [7, 8]
We performed survival analysis individually on two of the most common types of sarcoma included in the The Cancer Genome Atlas (TCGA) data set, undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcomas (DDLPS)
We combined the UPS and DDLPS data sets since these sarcomas exhibit similar clinical behavior. This analysis showed that increased WWTR1 (p = 0.0378) or YAP1 (p = 0.0302) expression correlated with reduced survival (Figure 1a and 1b)
Summary
TAZ(WWTR1 is the gene) and YAP are transcriptional coactivators and paralogues of one another normally inhibited by the Hippo pathway, a developmentally important signal transduction pathway that limits tissue growth and organ size. [1, 2] The Hippo pathway is a series of core serine/threonine kinases including the STE20-like protein kinases 1 and 2 (MST1/2) [3,4,5,6] and the large tumor suppressor 1 and 2 (LATS1/2) [7, 8]. [1, 2] The Hippo pathway is a series of core serine/threonine kinases including the STE20-like protein kinases 1 and 2 (MST1/2) [3,4,5,6] and the large tumor suppressor 1 and 2 (LATS1/2) [7, 8]. They form a complex with the MOB1A/B [9] and Salvador proteins [4] [6] which form a scaffold for the above kinases. Fusion of CAMTA1 to TAZ in the TAZ-CAMTA1 fusion protein constitutively activates the N terminus of TAZ by negating inhibitory effects of the Hippo pathway. [21]
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