Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2

Lim, Sai‐Kiang; Lu, Ssu Yi; Kang, Shinae; Tan, Hock Jin; Li, Fulin; Wee, Zhen Ning; Guan, Jye Swei; Chichili, Vishnu Priyanka Reddy; Sivaraman, J.; Putti, Thomas Choudary; Thike, Aye Aye; Tan, Puay Hoon; Sudol, Marius; Virshup, David M.; Chan, Siew Wee; Hong, Wanjin; Lim, Yoon Pin

doi:10.1158/0008-5472.can-15-3537

Cited by 68 publications

(154 citation statements)

References 37 publications

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“…The effect of WBP2 in enhancing the transcriptional co-activator functions of YAP likely involves the recruitment of factors that promote chromatin remodelling and productive transcriptional elongation61. In breast cancer cells, WBP2 cooperates with β-catenin and YAP/TAZ to drive TCF-mediated gene transcription downstream of WNT signalling62. Consistent with findings from other groups demonstrating that NHKs are only weakly responsive to WNT signals63, our NHK screen did not reveal any involvement of WNT signalling in controlling YAP activity in human epidermal SCs and in driving their clonal expansion.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

et al. 2017

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Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.

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Section: Discussionmentioning

confidence: 99%

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

et al. 2017

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“…WBP2 expression is significantly elevated in invasive ductal carcinoma and metastatic lesions [10]. High WBP2 expression correlates with poor prognosis in ER+ breast cancer patients [11].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, WBP2 behaves as an adaptor molecule of Pax8 [8], which is essential for the differentiation of thyroid cells [9]. It can also interact with YAP/TAZ as a bridge linking Hippo and Wnt pathways in breast cancer [10]. In ER+ breast cancer, WBP2 modulates tamoxifen sensitivity by facilitating G1/S transition [11].…”

Section: Introductionmentioning

confidence: 99%

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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“…2e). Emerging studies also show that Wnt signaling promotes breast cancer by blocking ITCH-mediated (an ubiquitin-conjugating enzyme) ubiquitin-dependent degradation of the YAP/TAZ transcriptional coactivator WBP2, suggesting WBP2/ITCH signaling functions to bridge the complex Wnt and Hippo signaling networks in breast cancer [79]. …”

Section: Introductionmentioning

confidence: 99%

WW domain-binding protein 2: an adaptor protein closely linked to the development of breast cancer

et al. 2017

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The WW domain is composed of 38 to 40 semi-conserved amino acids shared with structural, regulatory, and signaling proteins. WW domain-binding protein 2 (WBP2), as a binding partner of WW domain protein, interacts with several WW-domain-containing proteins, such as Yes kinase-associated protein (Yap), paired box gene 8 (Pax8), WW-domain-containing transcription regulator protein 1 (TAZ), and WW-domain-containing oxidoreductase (WWOX) through its PPxY motifs within C-terminal region, and further triggers the downstream signaling pathway in vitro and in vivo. Studies have confirmed that phosphorylated form of WBP2 can move into nuclei and activate the transcription of estrogen receptor (ER) and progesterone receptor (PR), whose expression were the indicators of breast cancer development, indicating that WBP2 may participate in the progression of breast cancer. Both overexpression of WBP2 and activation of tyrosine phosphorylation upregulate the signal cascades in the cross-regulation of the Wnt and ER signaling pathways in breast cancer. Following the binding of WBP2 to the WW domain region of TAZ which can accelerate migration, invasion and is required for the transformed phenotypes of breast cancer cells, the transformation of epithelial to mesenchymal of MCF10A is activated, suggesting that WBP2 is a key player in regulating cell migration. When WBP2 binds with WWOX, a tumor suppressor, ER transactivation and tumor growth can be suppressed. Thus, WBP2 may serve as a molecular on/off switch that controls the crosstalk between E2, WWOX, Wnt, TAZ, and other oncogenic signaling pathways. This review interprets the relationship between WBP2 and breast cancer, and provides comprehensive views about the function of WBP2 in the regulation of the pathogenesis of breast cancer and endocrine therapy in breast cancer treatment.

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Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2

Cited by 68 publications

References 37 publications

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

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

WW domain-binding protein 2: an adaptor protein closely linked to the development of breast cancer

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