A Peptide Mimicking VGLL4 Function Acts as a YAP Antagonist Therapy against Gastric Cancer

Shi, Jianzhong; Wang, Huizhen; Shi, Zhubing; Dong, Aisheng; Zhang, Wenjing; Song, Xiaomin; He, Feng; Wang, Yicui; Zhang, Zhenzhen; Wang, Wenjia; Wang, Xin; Guo, Tong; Li, Peixue; Zhao, Yun; Ji, Hongbin; Zhang, Lei; Zhou, Zhaocai

doi:10.1016/j.ccr.2014.01.010

Cited by 499 publications

(546 citation statements)

References 57 publications

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“…In contrast, expression of Yap is elevated in GC samples compared with matched noncancerous samples as previously described. 33 Furthermore, Yap is a confirmed predictor of poor prognosis in a variety of cancers 34 including gastric cancer. 33 Moreover, the IHC image demonstrated a significant elevated nuclear location of Yap in GC tissues compared with noncancerous tissues, consistent with previous research.…”

Section: Discussionmentioning

confidence: 99%

“…33 Furthermore, Yap is a confirmed predictor of poor prognosis in a variety of cancers 34 including gastric cancer. 33 Moreover, the IHC image demonstrated a significant elevated nuclear location of Yap in GC tissues compared with noncancerous tissues, consistent with previous research. 35 Remarkably, we observed a decreased expression of Fat4 with concomitant increased nuclear location of Yap in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

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Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells

Ma¹,

Cui²,

et al. 2015

Cancer Biology & Therapy

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Fat4 functions as a Hippo signaling regulator which is involved in mammalian tissue development, differentiation and tumorigenesis. Loss of Fat4 due to frequent gene mutation was detected in a variety of tumors including gastric cancer, where Fat4 was recognized as a tumor suppressor, repressing cancer cell proliferation and adhesion. However, the detailed mechanisms linking Fat4 to its diverse functions and clinicopathological characteristics in gastric cancer remain unclear. Here, we silenced Fat4 using Fat4-shRNA in gastric cancer cells and found that this suppression led to the increase in phosphorylated Yap and nuclear accumulation of Yap, which associated to the promoted proliferation, migration and cell cycle progression. Then we transfected a full-length Fat4 into the Fat4-silenced cells, and found the decrease in phosphorylated Yap and inhibition of the cell cycle progression. Intriguingly, Fat4 reduction also leads to the accumulation of cytoplasmic b-catenin via the loss of restraining to cytoplasmic Yap instead of b-catenin transcription promotion. The Fat4-silenced cells which were treated with 5-FU, Cisplatin, Oxaliplatin and Paclitaxel individually demonstrated less sensitivities to these chemotherapy drugs compared with the control cells. Furthermore, immunohistochemical analysis revealed that Fat4 expression was significantly reduced in gastric cancer tissues compared with adjacent noncancerous tissues, and negatively correlated with tumor infiltration, lymph node metastasis and cumulative survival rate. In conclusion, Fat4 expression is deceased in gastric cancer cells, leading to nuclear translocation of Yap and correlates with poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells

Ma¹,

Cui²,

et al. 2015

Cancer Biology & Therapy

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“…Both basic and clinical cancer research has implicated a role of YAP and TAZ in cancer initiation and development through suppressing cell apoptosis and promoting cell prolifieration (Moroishi et al 2015a). Concordantly, YAP and TAZ have been considered as therapeutic targets for a number of cancers (Liu-Chittenden et al 2012;Jiao et al 2014;Yu et al 2014;Zhou et al 2015b) as well as several other diseases . Notably, the R331W missense mutation of YAP has recently been linked to a germline risk in lung adenocarcinoma (Chen et al 2015a).…”

Section: The Yap/taz Transcriptional Programs and Their Functional Oumentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…Several studies have suggested a potential link between YAP/TAZ signaling and gastric cancer (12)(13)(14)(15). YAP expression is upregulated in gastric tumor samples compared to normal tissue, and the total amount of YAP expression as well as its nuclear localization are significantly correlated with poorer clinical outcomes (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…YAP expression is upregulated in gastric tumor samples compared to normal tissue, and the total amount of YAP expression as well as its nuclear localization are significantly correlated with poorer clinical outcomes (12)(13)(14). Moreover, a peptide mimicking the role of VGLL4 (a candidate for inhibiting the YAP-TEAD interaction) inhibits tumor growth in both xenograft and carcinogen-induced murine gastric tumor models (15).…”

Section: Introductionmentioning

confidence: 99%