WLS inhibits melanoma cell proliferation through the β‐catenin signalling pathway and induces spontaneous metastasis

Pei, Yang; Anastas, Jamie N.; Toroni, Rachel A.; Shinohara, Michi M.; Goodson, Jamie M.; Bosserhoff, Anja‐Katrin; Chien, Andy J.; Moon, Randall T.

doi:10.1002/emmm.201201486

Cited by 33 publications

(28 citation statements)

References 46 publications

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“…In order to gain further insight into the observed role for WNT5A in promoting the viability of both naive and BRAFi-resistant melanomas, we then focused on identifying signaling pathways acting downstream of WNT5A in melanoma. We and others have recently shown that activation of WNT/β-catenin-dependent signaling with WNT3A can inhibit the proliferation of melanoma cells in vitro and in vivo (24,30,31). Since several studies indicate that WNT5A can act as a negative regulator of WNT/β-catenin-dependent transcription (32,33), these data suggest that WNT5A might promote melanoma growth by inhibiting WNT/β-catenin signaling.…”

Section: Figurementioning

confidence: 80%

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

et al. 2014

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About half of all melanomas harbor a mutation that results in a constitutively active BRAF kinase mutant (BRAF V600E/K ) that can be selectively inhibited by targeted BRAF inhibitors (BRAFis). While patients treated with BRAFis initially exhibit measurable clinical improvement, the majority of patients eventually develop drug resistance and relapse. Here, we observed marked elevation of WNT5A in a subset of tumors from patients exhibiting disease progression on BRAFi therapy. WNT5A transcript and protein were also elevated in BRAFiresistant melanoma cell lines generated by long-term in vitro treatment with BRAFi. RNAi-mediated reduction of endogenous WNT5A in melanoma decreased cell growth, increased apoptosis in response to BRAFi challenge, and decreased the activity of prosurvival AKT signaling. Conversely, overexpression of WNT5A promoted melanoma growth, tumorigenesis, and activation of AKT signaling. Similarly to WNT5A knockdown, knockdown of the WNT receptors FZD7 and RYK inhibited growth, sensitized melanoma cells to BRAFi, and reduced AKT activation. Together, these findings suggest that chronic BRAF inhibition elevates WNT5A expression, which promotes AKT signaling through FZD7 and RYK, leading to increased growth and therapeutic resistance. Furthermore, increased WNT5A expression in BRAFi-resistant melanomas correlates with a specific transcriptional signature, which identifies potential therapeutic targets to reduce clinical BRAFi resistance.

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Section: Figurementioning

confidence: 80%

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

et al. 2014

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“…To confirm the role of Porcn function in Evi regulation without manipulating Wnt expression, we monitored Evi in the colon cancer cell line HCT116, that depends on Wnt secretion (Voloshanenko et al , 2013) and in the melanoma cell line A375, that expresses Wnt5A and Wnt10B endogenously (Yang et al , 2012). LGK974 treatment of HCT116 and A375 cells reduced Evi protein levels in a time‐dependent manner and depleted Evi below the detection limit after 24–48 h (Fig 2E) without reducing Evi mRNA levels (Fig EV2C and D).…”

Section: Resultsmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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“…In human, both WLS and SFRP2 have been implicated in various cancers. In particular, concomitant epigenetic silencing of SOX1 and SFRPs was reported in hepatocellular carcinoma [47][48][49][50]. It would be interesting to test whether SOX2 contributes to tumor development through transcriptionally controlling WLS and SFRP2 expression.…”

Section: Discussionmentioning

confidence: 97%

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

et al. 2016

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SOX2 is a key regulator of multiple types of stem cells, especially embryonic stem cells (ESCs) and neural progenitor cells (NPCs).Understanding the mechanism underlying the function of SOX2 is of great importance for realizing the full potential of ESCs and NPCs. Here, through genome-wide comparative studies, we show that SOX2 executes its distinct functions in human ESCs (hESCs) and hESC-derived NPCs (hNPCs) through cell type-and stage-dependent transcription programs. Importantly, SOX2 suppresses non-neural lineages in hESCs and regulates neurogenesis from hNPCs by inhibiting canonical Wnt signaling. In hESCs, SOX2 achieves such inhibition by direct transcriptional regulation of important Wnt signaling modulators, WLS and SFRP2. Moreover, SOX2 ensures pluripotent epigenetic landscapes via interacting with histone variant H2A.Z and recruiting polycomb repressor complex 2 to poise developmental genes in hESCs. Together, our results advance our understanding of the mechanism by which cell type-specific transcription factors control lineage-specific gene expression programs and specify cell fate.

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WLS inhibits melanoma cell proliferation through the β‐catenin signalling pathway and induces spontaneous metastasis

Cited by 33 publications

References 46 publications

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors

ERAD‐dependent control of the Wnt secretory factor Evi

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

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