Regulation of the Hippo Pathway Transcription Factor TEAD

Lin, Kai; Park, Hyun Woo; Guan, Kun Liang

doi:10.1016/j.tibs.2017.09.003

Cited by 248 publications

(229 citation statements)

References 90 publications

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“…These findings were similar to those in recent reports which showed that WBP2 can directly interact with or affect YAP through WW domains [18][19][20]. The TEA domain (TEAD) family of transcription factors (TEAD1-4) play an important role in tumorigenesis by regulating various cellular processes, including cell growth, proliferation, differentiation, and survival [21]. YAP in conjunction with TEAD1-4 mediate major physiological functions of the Hippo pathway [22,23].…”

Section: Discussionsupporting

confidence: 90%

WBP2 Downregulation Inhibits Proliferation by Blocking YAP Transcription and the EGFR/PI3K/Akt Signaling Pathway in Triple Negative Breast Cancer

Song¹,

Wu²,

Xie³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Dysregulated expression of WW domain-binding protein 2 (WBP2) is associated with poor prognosis in ER+ breast cancer patients. However, its role in triple negative breast cancer (TNBC) has not been previously assessed. Therefore, we aimed to elucidate the functional mechanism of WBP2 in TNBC cells. Methods: qRT-PCR, western blotting, and immunohistochemical staining were used to evaluate WBP2 expression in TNBC patient tumors and cell lines. HCC1937 and MDA-MB-231 cells transiently transfected with WBP2 small interfering RNA (siRNA), miR-613 mimics, or miR-613 inhibitors were subject to assays for cell viability, apoptosis and cell cycle distribution. Co-immunoprecipitation, western blotting or qRT-PCR were employed to monitor changes in signaling pathway-related genes and proteins. Luciferase assays were performed to assess whether WBP2 is a direct target of miR-613. The effect of miR-613 on tumor growth was assessed in vivo using mouse xenograft models. Results: The expression of WBP2 was upregulated in TNBC tissues and cells. Expression of WBP2 was significantly correlated with Ki67 in TNBC patients. Knockdown of WBP2 inhibited cellular proliferation, promoted apoptosis, and induced cell cycle arrest of TNBC cells. miR-613 directly bound to the 3’-untranslated region (3’-UTR) of WBP2 and regulated the expression of WBP2. Moreover, miR-613 reduced the expression of WBP2 and suppressed tumor growth of TNBC cells in vivo. Knockdown of WBP2 inhibited YAP transcription and the EGFR/PI3K/Akt signaling pathway in TNBC cells, and these effects were reversed by inhibition of miR-613. Conclusion: WBP2 overexpression is associated with the poor prognosis of TNBC patients and the miR-613-WBP2 axis represses TNBC cell growth by inactivating YAP-mediated gene expression and the EGFR/PI3K/Akt signaling pathway.

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Section: Discussionsupporting

confidence: 90%

WBP2 Downregulation Inhibits Proliferation by Blocking YAP Transcription and the EGFR/PI3K/Akt Signaling Pathway in Triple Negative Breast Cancer

Song¹,

Wu²,

Xie³

et al. 2018

Cell Physiol Biochem

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“…TEADs are DNA‐binding proteins that can be activated by YAP1 and work as transcription factors . YAP1 has been demonstrated to promote tumorigenesis by activating TEAD in breast cancers, cholangiocarcinoma, and renal cell carcinoma .…”

Section: Discussionmentioning

confidence: 99%

Helicobacter pylori‐induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL‐1β expression

Shen

Liang

et al. 2019

Cancer Medicine

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Gastric cancer (GC) is one of the most common and malignant pathologies, and a significant portion of GC incidences develops from Helicobacter pylori (Hp) ‐induced chronic gastritis. Although the exact mechanisms of GC are complex and poorly understood, gastric carcinogenesis is a good model to investigate how inflammation and infection collaboratively promote tumorigenesis. Yes‐associated protein 1 (YAP1) is the key effector of the Hippo pathway, which is silenced in most human cancers. Herein, we verified the tumor‐promoting effect of YAP1 in vitro, in vivo, and in human specimens. We revealed that YAP1 displays nuclear translocation and works with TEAD to activate transcription of the crucial inflammatory cytokine IL‐1β in gastric cells infected with Hp . As IL‐1ß accounts for inflammation‐associated tumorigenesis, this process can lead to gastric carcinogenesis. Thus, in addition to activating proliferation genes, YAP1 also plays a major role in inflammation amplification by activating inflammatory cytokine genes. Excitingly, our research demonstrates that transfection of mutant plasmid YAP‐5SA/S94A or addition of the drug verteporfin, both of which are thought to disrupt the YAP1‐TEAD interaction, can arrest the carcinogenesis process. These findings can provide new approaches to GC treatment.

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“…When not phosphorylated by the Hippo core cassette, YAP/TAZ/ Yki translocate to the nucleus and associate with transcriptional regulators including those of the TEAD family to induce gene expression (Lin et al 2017). Consequently, Hippo pathway activity inhibits YAP/TAZ/Yki target gene expression.…”

Section: Rhobtb Lkb1 (Stk11) Hippo Pathway Ubiquitinationmentioning

confidence: 99%

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

Nguyen

Ralbovska

Kugler

2020

G3 Genes|Genomes|Genetics

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The Hippo pathway regulates growth and apoptosis. We identify RhoBTB proteins as novel regulators of Hippo signaling. RhoBTB depletion in the Drosophila wing disc epithelium cooperated with Yki to drive hyperplasia into neoplasia. Depletion of RhoBTB2 caused elevated YAP activity in human cells. RhoBTB2 deficiency resulted in increased colony formation in assays for anchorage-independent growth. We provide evidence that RhoBTBs acts on Hippo signaling through regulation of the kinase LKB1. LKB1 protein levels were reduced upon RhoBTB2 depletion, which correlated with increased LKB1 ubiquitination. Restoring LKB1 levels rescued loss of RhoBTB in Drosophila. Our results suggest that RhoBTB-dependent LKB1 regulation may contribute to its tumor-suppressive function.

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Regulation of the Hippo Pathway Transcription Factor TEAD

Cited by 248 publications

References 90 publications

WBP2 Downregulation Inhibits Proliferation by Blocking YAP Transcription and the EGFR/PI3K/Akt Signaling Pathway in Triple Negative Breast Cancer

WBP2 Downregulation Inhibits Proliferation by Blocking YAP Transcription and the EGFR/PI3K/Akt Signaling Pathway in Triple Negative Breast Cancer

Helicobacter pylori‐induced YAP1 nuclear translocation promotes gastric carcinogenesis by enhancing IL‐1β expression

RhoBTB Proteins Regulate the Hippo Pathway by Antagonizing Ubiquitination of LKB1

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