The emerging roles of WBP2 oncogene in human cancers

Tabatabaeian, Hossein; Rao, Angad; Ramos, Alisha; Chu, Tinghine; Sudol, Marius; Lim, Yoon Pin

doi:10.1038/s41388-020-1318-0

Cited by 22 publications

(38 citation statements)

References 98 publications

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“…Patients with higher WBP2 expression had poorer overall and disease-free survival 15 . WBP2 is increasingly implicated in other cancers, such as skin, brain, and liver 10 .…”

Section: Introductionmentioning

confidence: 99%

“…W W domain- B inding P rotein 2 (WBP2) was first identified as a cognate ligand of the WW domain of YAP 8 , 9 . WBP2’s transcription co-activator function is important to cancer 10 . Binding of WBP2 to E6AP potentiated Estrogen and Progesterone Receptor co-activation 11 by binding to the phosphorylated form of RNA polymerase II and histone acetyltransferase p300 12 .…”

Section: Introductionmentioning

confidence: 99%

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Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer

Lim

Tabatabaeian

et al. 2020

Cell Death Dis

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WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein-protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATSindependent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS-and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3′UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.

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“…Patients with higher WBP2 expression had poorer overall and disease-free survival 15 . WBP2 is increasingly implicated in other cancers, such as skin, brain, and liver 10 .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer

Lim

Tabatabaeian

et al. 2020

Cell Death Dis

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“…The upstream protein WWC3 of the Hippo pathway was identi ed as WBP2 binding protein Previous studies suggested that WBP2 localizes within the nucleus of breast cancer cells and acts as a co-activator of YAP to promote the transcription of downstream genes [17]. Interestingly, we found that WBP2 was localized within the cytoplasm of lung cancer cells, and based on this, we speculated that WBP2 may modulate the Hippo pathway in a YAP-indirect-dependent manner.…”

Section: Cascade Phosphorylation Of the Mst-lats Complex In The Hippomentioning

confidence: 67%

“…WBP2 can bind to estrogen and progesterone receptors and can act as a co-activator of estrogen receptor (ER) and progesterone receptor (PR) hormone signaling transduction [12][13][14][15]. Additionally, the synergetic effect of WBP2 and YAP/TAZ in the nucleus plays an important role in promoting the proliferation and invasion of breast cancer cells by regulating the activities of classical signal pathways in both tumor tissues and normal tissues [16][17][18][19][20]. However, the expression pattern of WBP2 in lung cancer and the ability of this protein to regulate the activity of the Hippo pathway in an indirect manner that is dependent upon YAP both remain unreported.…”

Section: Introductionmentioning

confidence: 99%

WBP2 Negatively Regulates Hippo Pathway By Competitively Binding To WWC3 With LATS1 To Promote The Malignant Phenotype Of Non-Small Cell Lung Cancer

Han¹,

Rong²,

Lin³

et al. 2020

Preprint

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Background: WW domain binding protein-2 (WBP2) can function as a YAP/TAZ co-activator and play a vital role in promoting breast cancer progression. However, the expression and potential molecular mechanism of WBP2 in the context of lung cancer are not fully understood. Methods: Expression and subcellular localization of WBP2 in clinical samples and in lung cancer cell lines were analyzed with respect to various clinical pathological parameters using Chi-square tests. We used a series of cell function experiments and tumor formation experiments in nude mice to verify the effect of WBP2 on tumor cell proliferation and invasion. Dual-directional regulation of WBP2 expression, immunoprecipitation, luciferase reporter assays, and quantitative PCR analyses were used to explore the regulatory mechanisms and identify associated molecular markers.Results: We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the pTNM stage, lymph node metastasis, and poor prognosis of patients. Additionally, gain and loss of function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 with LATS1 through its PPxY motifs to inhibit the formation of the WWC3-LATS1 complex, reduce the phosphorylation level of LATS1, and ultimately promote YAP nuclear translocation to suppress the activity of the Hippo pathway. Conclusions: From the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.

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“…Notably, several wellknown cancer migration and progression drivers were downregulated (Fig. 4B), including TRIM47 which mediates cancer migration 29 , the bona fide oncoprotein and potential biomarker WBP2 30 , and frequently highly amplified oncogene FNDC3B 31 . None of these proteins have previously been functionally linked to BRAT1.…”

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confidence: 99%

Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

Cui¹,

Dwyer²,

Liu³

et al. 2020

Preprint

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Natural products are an indispensable source of lifesaving medicine, but natural product-based drug discovery often suffers from scarce natural supply and unknown mode of action. The study and development of anticancer curcusone diterpenes fall into such a dilemma. Meanwhile, many biologically-validated disease targets are considered “undruggable” due to the lack of enzymatic activity and/or predicted small molecule binding sites. The oncogenic BRCA1-associated ATM activator 1 (BRAT1) belongs to such an “undruggable” category. Here, we report our synthetic and chemoproteomics studies of the curcusone diterpenes that culminate in an efficient total synthesis and the identification of BRAT1 as a cellular target. We demonstrate for the first time that BRAT1 can be inhibited by a small molecule (curcusone D), resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

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The emerging roles of WBP2 oncogene in human cancers

Cited by 22 publications

References 98 publications

Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer

Hippo/MST blocks breast cancer by downregulating WBP2 oncogene expression via miRNA processor Dicer

WBP2 Negatively Regulates Hippo Pathway By Competitively Binding To WWC3 With LATS1 To Promote The Malignant Phenotype Of Non-Small Cell Lung Cancer

Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

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