WBP2 modulates G1/S transition in ER+ breast cancer cells and is a direct target of miR-206

Ren, Yuying; Wang, Huijun; Zhang, Yongqing; Liu, Yanbing

doi:10.1007/s00280-017-3302-0

Cited by 32 publications

(34 citation statements)

References 20 publications

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“…High WBP2 expression correlates with poor prognosis in ER+ breast cancer patients [11]. However, the expression and molecular mechanism of WBP2 in TNBC have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

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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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“…High WBP2 expression correlates with poor prognosis in ER+ breast cancer patients [11]. However, the expression and molecular mechanism of WBP2 in TNBC have not been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…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]. However, the roles for WBP2 in TNBC, the hormone receptor absent subtype, remain unclear.…”

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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“…miR-148a and miR-152 reduced tamoxifen resistance in ER+BC via direct down-regulating the activated leukocyte cell adhesion molecule (ALCAM) (429). miR-206 was elevated in ER+BC cell lines (161) and its knock-down induced resistance to tamoxifen, while its overexpression reduced it by regulating G1/S-related proteins (430). miR-26a/b levels were lower in tamoxifen-resistant ER+BC and the inactivation of miR-26a/b decreased tamoxifen responsiveness of cancer cells (431).…”

Section: Drugs/non-coding Rnas Subnetworkmentioning

confidence: 99%

The Network of Non-coding RNAs in Cancer Drug Resistance

et al. 2018

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Non-coding RNAs (ncRNAs) have been implicated in most cellular functions. The disruption of their function through somatic mutations, genomic imprinting, transcriptional and post-transcriptional regulation, plays an ever-increasing role in cancer development. ncRNAs, including notorious microRNAs, have been thus proposed to function as tumor suppressors or oncogenes, often in a context-dependent fashion. In parallel, ncRNAs with altered expression in cancer have been reported to exert a key role in determining drug sensitivity or restoring drug responsiveness in resistant cells. Acquisition of resistance to anti-cancer drugs is a major hindrance to effective chemotherapy and is one of the most important causes of relapse and mortality in cancer patients. For these reasons, non-coding RNAs have become recent focuses as prognostic agents and modifiers of chemo-sensitivity. This review starts with a brief outline of the role of most studied non-coding RNAs in cancer and then highlights the modulation of cancer drug resistance via known ncRNAs based mechanisms. We identified from literature 388 ncRNA-drugs interactions and analyzed them using an unsupervised approach. Essentially, we performed a network analysis of the non-coding RNAs with direct relations with cancer drugs. Within such a machine-learning framework we detected the most representative ncRNAs-drug associations and groups. We finally discussed the higher integration of the drug-ncRNA clusters with the goal of disentangling effectors from downstream effects and further clarify the involvement of ncRNAs in the cellular mechanisms underlying resistance to cancer treatments.

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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).…”

mentioning

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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WBP2 modulates G1/S transition in ER+ breast cancer cells and is a direct target of miR-206

Abstract: Based on these findings, we infer that the miR-206/WBP2 axis can modulate tamoxifen sensitivity via regulating G1/S progression in ER+ breast cancer.

Cited by 32 publications

References 20 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

The Network of Non-coding RNAs in Cancer Drug Resistance

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

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