The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Abstract

f Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). P rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1, 2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known. It is expected that understanding the molecular mechanisms and identifying the molecular pathways underlying the acquisition of castration resistance in prostate cancer are critical for the design of therapeutic strategies and may lead to the discovery of novel targets.The Hippo signaling pathway, originally defined by fly geneticists, plays an important role in tumorigenesis by regulating cell proliferation and apoptosis (3-7). In mammals, protein kinases Mst1/2 (mammalian sterile 20-like 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2) and the adaptor proteins WW45 (WW domain-containing protein) and Mob1 (Mps one binder 1) are the Hippo core components. These proteins form complexes to regulate their activity mainly through phosphorylation. The Hippo core is tumor suppressive and exerts its function by phosphorylating and inactivating YAP (Yes-associated protein) and its paralog, TAZ (transcriptional coactivator with a PDZ-bi...

Markers of Hippo-Pathway Activity in Tumor Forming Liver Lesions

“…In line with in vitro and murine-model results, YAP over-expression and/or nuclear accumulation has been detected in several human malignant tumors such as prostate, colorectal and lung cancer as well as HCC [4,[7][8][9][10][11][12]. In the latter, YAP expression also was also found to influence the prognosis and was associated with poorer tumor cell differentiation [13,14].…”

Label free quantitative proteomics reveals the role of miR-200b in androgen-independent prostate cancer cells

“…Some of these proteins were reported to be related with AIPC. YAP was recently identified as a novel regulator of prostate cancer cell motility, invasion, and androgen independent growth [21,22] and was considered as a potential therapeutic target for metastatic AIPC. YAP1 is a transcriptional regulator which can act both as a co-activator and a co-repressor; it is a critical downstream regulatory target in the Hippo signaling pathway that plays a Fig.…”

Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome

“…Its deregulation is frequently observed in many types of malignancies, suggesting that alterations of this signaling are connected with cancer progression and patient survival (7)(8)(9)21,33,34). The core components of this pathway include MST1/2, SAV1, LATS1/2 and MOB1 proteins (10,12,15).…”

“…The reported associations between decreased levels of either miR-509-3p or miR-138 in the studied types of cancer and poorer patient outcome (63)(64)(65), consolidating the influence of YAP1 in tumor progression. In fact, the contribution of YAP1 protein in tumor progression is so important that it was acknowledged as a pivotal molecular target in modern cancer treatment (5,34,38,51,52,66,67). Some authors found an association between YAP1 overexpression and chemoresistance of cancer cells, e.g., in head and neck cancer cases resistant to cetuximab (57), resistance to RAF-and MEK-targeted therapy (33), 5-FU chemotherapy-resistant colon cancer (68) and osteosarcoma resistance (69).…”