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

Walko, Gernot; Woodhouse, Samuel; Pisco, Angela Oliveira; Rognoni, Emanuel; Liakath‐Ali, Kifayathullah; Lichtenberger, Beate M.; Mishra, Ajay; Telerman, Stéphanie B.; Viswanathan, Priyalakshmi; Logtenberg, Meike E. W.; Renz, Lisa M.; Donati, Giacomo; Quist, Sven R; Watt, Fiona M.

doi:10.1038/ncomms14744

Cited by 85 publications

(172 citation statements)

References 69 publications

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“…Transitions between stemness and differentiation states are determined by transcriptional and epigenetic changes that shape the genomic landscape of epithelial cells, affecting the differential binding of transcriptional activators and repressors to genes that participate in stem cell-renewal and the initiation of terminal differentiation [1][2][3] . YAP1 and its paralog TAZ (WWTR1) are co-transcriptional regulators downstream of the Hippo pathway 4,5 that are essential for skin homeostasis and epithelial stem cell maintenance [6][7][8][9] . YAP1 and TAZ are also implicated in skin basal (BCC) and squamous (SCC) cell carcinoma formation 7,10,11 .…”

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confidence: 99%

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

et al. 2020

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The Hippo TEAD-transcriptional regulators YAP1 and TAZ are central for cell renewal and cancer growth; however, the specific downstream gene networks involved in their activity are not completely understood. Here we introduce TEADi, a genetically encoded inhibitor of the interaction of YAP1 and TAZ with TEAD, as a tool to characterize the transcriptional networks and biological effects regulated by TEAD transcription factors. Blockage of TEAD activity by TEADi in human keratinocytes and mouse skin leads to reduced proliferation and rapid activation of differentiation programs. Analysis of gene networks affected by TEADi and YAP1/TAZ knockdown identifies KLF4 as a central transcriptional node regulated by YAP1/ TAZ-TEAD in keratinocyte differentiation. Moreover, we show that TEAD and KLF4 can regulate the activity of each other, indicating that these factors are part of a transcriptional regulatory loop. Our study establishes TEADi as a resource for studying YAP1/TAZ-TEAD dependent effects.

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confidence: 99%

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

et al. 2020

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“…WBP2 is degraded by itchy E3 ubiquitin protein ligase (ITCH E3 ligase) to prevent aberrant growth but is protected from ITCH and activated by Wnt oncogenic signaling to drive TCF/␤-cateninmediated transcription to promote breast cancer (21). Recent studies identified WBP2 as a key cofactor of YAP driving the clonal expansion of normal and neoplastic human epidermal stem cells via TEA domain transcription factor (TEAD) transcription factors (24), in modulating G 1 /S cell cycle transition in estrogen receptorϩ breast cancer cells via a micro RNA-based mechanism (25) and crucial for normal glutamatergic synapses in the cochlea and hearing (26).…”

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confidence: 99%

The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway

Lim

et al. 2018

Journal of Biological Chemistry

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The transcriptional coactivator WW domain-binding protein 2 (WBP2) is an emerging oncogene and serves as a node between the signaling protein Wnt and other signaling molecules and pathways, including epidermal growth factor receptor, estrogen receptor/progesterone receptor, and the Hippo pathway. The upstream regulation of WBP2 is well-studied, but its downstream activity remains unclear. Here, we elucidated WBP2's role in triple-negative breast cancer (TNBC), in which Wnt signaling is predominantly activated. Using RNAi coupled with RNA-Seq and MS analyses to identify Wnt/WBP2-and WBP2-dependent targets in MDA-MB-231 TNBC cells, we found that WBP2 is required for the expression of a core set of genes in Wnt signaling. These included AXIN2, which was essential for Wnt/WBP2-mediated breast cancer growth and migration. WBP2 also regulated a much larger set of genes and proteins independently of Wnt, revealing that WBP2 primes cells to Wnt activity by up-regulating G protein pathway suppressor 1 (GPS1) and TRAF2-and NCK-interacting kinase (TNIK). GPS1 activated the c-Jun N-terminal kinase (JNK)/Jun pathway, resulting in a positive feedback loop with TNIK that mediated Wnt-induced AXIN2 expression. WBP2 promoted TNBC growth by integrating JNK with Wnt signaling, and its expression profoundly influenced the sensitivity of TNBC to JNK/TNIK inhibitors. In conclusion, WBP2 links JNK to Wnt signaling in TNBC. GPS1 and TNIK are constituents of a WBP2initiated cascade that primes responses to Wnt ligands and are also important for TNBC biology. We propose that WBP2 is a potential drug target for JNK/TNIK-based precision medicine for managing TNBC.

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“…Subsequent studies have elucidated its role as a transcription coactivator in estrogen receptor/progesterone receptor hormone signaling (5)(6)(7) and as a tyrosine kinase substrate in epidermal growth factor receptor signaling (8). It interacts with transcriptional coactivator with PDZ binding motif (TAZ), Yorkie (Drosophila YAP), and YAP, which are key downstream effectors of the Hippo pathway and which facilitate their oncogenic and growth-promoting properties (9)(10)(11). WBP2 partners with YAP/TEA domain transcription factor (TEAD) to promote epidermal proliferation required for development and wound healing (11).…”

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confidence: 99%

Phosphorylation of E‐box binding USF‐1 by PI3K/AKT enhances its transcriptional activation of the WBP2 oncogene in breast cancer cells

Ramos

Miow

et al. 2018

The FASEB Journal

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WW domain binding protein 2 (WBP2), a transcriptional coactivator, plays a vital role in breast tumorigenesis. It positively regulates estrogen receptor, Hippo, and Wnt pathways, which subsequently enhance the transcription of downstream target genes contributing to cancer. Understanding the regulation of the expression and activity of WBP2 oncoprotein has implication in cancer therapy. We have previously reported that WBP2 is regulated at the post-translational and post-transcriptional levels. However, its regulation at the transcriptional level is not known. In this study, the minimal promoter region of WBP2 that is critical for its transcription was identified. The E-box motif in the WBP2 promoter was demonstrated to be essential for its transcription. The E-box binding protein upstream stimulatory factor 1 (USF-1) was discovered to be a key transcription factor for WBP2 by yeast one-hybrid analysis and was validated through reporter and chromatin immunoprecipitation assays and tandem mass spectrometry, which also suggested that USF-1 acts by regulating a network of genes, in addition to WBP2, associated with cell movement, proliferation, cell-cycle, and survival cellular processes. USF-1 is overexpressed in majority of the breast cancer cell lines and tissues tested, and has profound effects on cancer cell proliferation. USF-1-mediated transcription of WBP2 was demonstrated to be inducible by insulin, which led to AKT-mediated phosphorylation of USF-1 that modulated its ability to bind to the WBP2 promoter and activate its transcription. This study sheds new light onto the regulation of the WBP2 oncogene at the transcriptional level by a novel oncogenic transcription factor, USF-1. USF-1 is a potential drug target for treatment of WBP2-positive breast cancer.-Ramos, A., Miow, Q. H., Liang, X., Lin, Q. S., Putti, T. C., Lim, Y. P. Phosphorylation of E-box binding USF-1 by PI3K/AKT enhances its transcriptional activation of the WBP2 oncogene in breast cancer cells.

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

Cited by 85 publications

References 69 publications

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

YAP1/TAZ-TEAD transcriptional networks maintain skin homeostasis by regulating cell proliferation and limiting KLF4 activity

The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway

Phosphorylation of E‐box binding USF‐1 by PI3K/AKT enhances its transcriptional activation of the WBP2 oncogene in breast cancer cells

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