The Hippo signaling pathway plays pivotal roles in controlling both cell growth and organ size, emerging as a new paradigm in tumor suppression. Yes-associated protein (YAP) functions as a potent transcription co-activator and is a major downstream target tightly regulated by the Hippo pathway. Inactivation of the Hippo signaling induces YAP-mediated activation of various target genes that functionally causes cellular proliferation and outgrowth of organ size. Recently, YAP has been implicated as a bona fide oncogene in solid tumors, but little is known about its exact molecular mechanism in carcinogenesis.
We discuss the latest important findings in the Hippo signaling pathway and the possible means of developing potential cancer therapeutics by targeting multiple sites along the Hippo pathway.
An overview of the emerging roles of YAP and Hippo signaling in oncogenesis and the possible ways of developing cancer therapies against the pathway components, downstream targets or interconnected pathways.
YAP is a key oncogenic driver in liver carcinogenesis and deregulation of the Hippo pathway causes tumor formation and malignancy. Targeting YAP and cognate downstream signaling targets may have clinical utility in cancer therapies.
"c-Myc and Cyclin E are both confirmed target proteins of Fbxw7. YAP functions as a transcriptional coactivator involved in the regulation of cell growth, proliferation, and apoptosis
. Fbxw7 knockdown led to c-Myc and Cyclin E accumulation in Hep3B cells and Fbxw7 overexpression decreased the levels of both proteins in HepG2 cells (Figure
[Show abstract][Hide abstract] ABSTRACT: Background
The E3 ubiquitin ligase Fbxw7 functions as a general tumor suppressor by targeting several well-known oncoproteins for ubiquitination and proteasomal degradation. However, the clinical significance of Fbxw7 and the mechanisms involved in the anti-cancer effect of Fbxw7 in HCC are not clear.
The Fbxw7 and YAP expression in 60 samples of surgical resected HCC and matched normal tumor-adjacent tissues were assessed using IHC or immunoblotting. Flow cytometry, caspase 3/7 activity assay, BrdU cell proliferation assay and MTT assay were used to detect proliferation and apoptosis of HCC cells. The regulatory effect of Fbxw7 on YAP in HCC cells was confirmed by qRT-PCR, immunoblotting and immunofluorescence. Co-immunoprecipitation was used to analyze interaction between YAP and Fbxw7. Nude mice subcutaneous injection, Ki-67 staining and TUNEL assay were used to evaluate tumor growth and apoptosis in vivo.
In this study, we found that Fbxw7 expression was impaired in HCC tissues and loss of Fbxw7 expression was correlated with poor clinicopathological features including large tumor size, venous infiltration, high pathological grading and advanced TNM stage. Additionally, we demonstrated that patients with positive Fbxw7 expression had a better 5-year survival and Fbxw7 was an independent factor for predicting the prognosis of HCC patients. We confirmed that Fbxw7 inhibited HCC by inducing both apoptosis and growth arrest. Elevated YAP expression was observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated that Fbxw7 was inversely associated with YAP protein expression in HCC tissues. We also found that Fbxw7 regulated YAP protein abundance by targeting YAP for ubiquitination and proteasomal degradation in HCC. Furthermore, restoring YAP expression partially abrogated Fbxw7 induced HCC cell apoptosis and growth arrest in vitro and in vivo.
These results indicate that Fbxw7 may serve as a prognostic marker and that YAP may be a potential target of Fbxw7 in HCC.
Molecular Cancer 05/2014; 13(1):110. DOI:10.1186/1476-4598-13-110 · 4.26 Impact Factor
"Heart specific expression of Mst1 leads to dilated cardiomyopathy with reduction in cell density in heart . Liver specific removal of Mst1/Mst2 in newborn mice results in liver enlargement and formation of hepatocellular carcinoma and cholangiocarcinoma [12,19-21]. Similarly, in mouse intestines and pancreas, inactivation of Mst1/Mst2 leads to intestinal stem cell overproliferation, colonic tumorigenesis and pancreas overgrowth [22-24], suggesting important roles of Mst1/Mst2 in organ size control and tumorigenesis. "
[Show abstract][Hide abstract] ABSTRACT: The Hippo pathway is an evolutionary conserved pathway that involves cell proliferation, differentiation, apoptosis and organ size regulation. Mst1 and Mst2 are central components of this pathway that are essential for embryonic development, though their role in controlling embryonic stem cells (ES cells) has yet to be exploited. To further understand the Mst1/Mst2 function in ES cell pluripotency and differentiation, we derived Mst1/Mst2 double knockout (Mst-/-) ES cells to completely perturb Hippo signaling. We found that Mst-/- ES cells express higher level of Nanog than wild type ES cells and show differentiation resistance after LIF withdrawal. They also proliferate faster than wild type ES cells. Although Mst-/- ES cells can form embryoid bodies (EBs), their differentiation into tissues of three germ layers is distorted. Intriguingly, Mst-/- ES cells are unable to form teratoma. Mst-/- ES cells can differentiate into mesoderm lineage, but further differentiation to cardiac lineage cells is significantly affected. Microarray analysis revealed that ligands of non-canonical Wnt signaling, which is critical for cardiac progenitor specification, are significantly repressed in Mst-/- EBs. Taken together our results showed that Mst1/Mst2 are required for proper cardiac lineage cell development and teratoma formation.
PLoS ONE 11/2013; 8(11):e79867. DOI:10.1371/journal.pone.0079867 · 3.23 Impact Factor
"Overexpression of YAP1 leads to loss of contact inhibition and increases the organ size (Huang et al. 2005; Camargo et al. 2007). Dysregulation of YAP1 has been identified in various types of cancer (Yuan et al. 2008; Liu et al. 2010; Wu et al. 2010; Orr et al. 2011; Zhang et al. 2011; Diep et al. 2012). Because of its crucial function in tissue growth and tumor development, YAP1 and its regulation have been studied extensively. "
[Show abstract][Hide abstract] ABSTRACT: Through an shRNA-mediated loss-of-function screen, we identified PTPN14 as a potential tumor suppressor. PTPN14 interacts with yes-associated protein 1 (YAP1), a member of the hippo signaling pathway. We showed that PTPN14 promotes the nucleus-to-cytoplasm translocation of YAP1 during contact inhibition and thus inhibits YAP1 transactivation activity. Interestingly, PTPN14 protein stability was positively controlled by cell density. We identified the CRL2(LRR1) (cullin2 RING ubiquitin ligase complex/leucine-rich repeat protein 1) complex as the E3 ligase that targets PTPN14 for degradation at low cell density. Collectively, these data suggest that PTPN14 acts to suppress cell proliferation by promoting cell density-dependent cytoplasmic translocation of YAP1.
Genes & development 09/2012; 26(17):1959-71. DOI:10.1101/gad.192955.112 · 10.80 Impact Factor
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