ETS‐1/RhoC signaling regulates the transcription factor c‐Jun in melanoma

Spangler, Barbara; Kappelmann‐Fenzl, Melanie; Schittek, Birgit; Meierjohann, Svenja; Vardimon, Lily; Bosserhoff, Anja‐Katrin; Kuphal, Silke

doi:10.1002/ijc.26277

Cited by 31 publications

(24 citation statements)

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“…3D). These results support the previously reported crosstalk between the AP-1 (cJUN and cFOS) and ETS-1 transcription factors (33, 34). Finally, in MDA-231 cells, chromatin immunoprecipitation (ChIP) with an ETS-1 antibody identified a binding region of ETS-1 in the IL8 promoter, and ETS-1 was abrogated by treatment with the MEK inhibitor selumetinib (Supplementary Fig.…”

Section: Resultssupporting

confidence: 93%

Activation of MAPK Pathways due to DUSP4 Loss Promotes Cancer Stem Cell-like Phenotypes in Basal-like Breast Cancer

et al. 2013

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Basal-like breast cancer (BLBC) is an aggressive disease that lacks a clinically-approved targeting therapy. Traditional chemotherapy is effective in BLBC, but it spares the cancer stem cell (CSC)-like population which is likely to contribute to cancer recurrence after the initial treatment. DUSP4 is a negative regulator of the MAPK pathway that is deficient in highly aggressive BLBCs treated with chemotherapy, leading to aberrant MAPK activation and resistance to taxane-induced apoptosis. Herein, we investigated how DUSP4 regulates the MEK and JNK pathways in modifying CSC-like behavior. DUSP4 loss increased mammosphere formation and the expression of the CSC-promoting cytokines IL-6 and IL-8. These effects were caused in part by loss of control of the MEK and JNK pathways and involved downstream activation of the ETS-1 and c-JUN transcription factors. Enforced expression of DUSP4 in reduced the CD44+/CD24- population in multiple BLBC cell lines in a MEK-dependent manner, limiting tumor formation of claudin-low SUM159PT cells in mice. Our findings support the evaluation of MEK and JNK pathway inhibitors as therapeutic agents in BLBC in order to eliminate the CSC population.

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Section: Resultssupporting

confidence: 93%

Activation of MAPK Pathways due to DUSP4 Loss Promotes Cancer Stem Cell-like Phenotypes in Basal-like Breast Cancer

et al. 2013

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“…We were interested in determining which signaling pathways may be implicated in vemurafenib-induced activation of c-JUN through the reduction of SPRY regulation. Previous studies show that SPRY4, the downregulation of which is sufficient to increase c-JUN, suppresses RAS activation (38), which also activates multiple signaling pathways impinging on c-JUN, including the JNK (39) and the Rho-ROCK (Rho-associated protein kinase) pathways (40,41). We found that ROCK inhibition counteracted the vemurafenib-induced increase in c-JUN abundance and activity (Fig.…”

Section: C-jun Mediates Cell Survival During Early Drug Adaptationmentioning

confidence: 51%

The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma

et al. 2015

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Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xenografts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathway), increased expression of JUN and reduced expression of LEF1. This coincided with a switch in phenotype that resembled an epithelial-mesenchymal transition (EMT). In cultured cells, these BRAF inhibitor-induced changes were reversed upon removal of the drug. Knockdown of SPROUTY4 was sufficient to increase the abundance of c-JUN in the absence of drug treatment. Overexpressing c-JUN in drug-naïve melanoma cells induced similar EMT-like phenotypic changes to BRAF inhibitor treatment, whereas knocking down JUN abrogated the BRAF inhibitor-induced early adaptive changes associated with resistance and enhanced cell death. Combining the BRAF inhibitor with an inhibitor of c-JUN amino-terminal kinase (JNK) reduced c-JUN phosphorylation, decreased cell migration, and increased cell death in melanoma cells. Gene expression data from a panel of melanoma cell lines and a patient cohort showed that JUN expression correlated with a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.

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“…In recent studies with melanoma cells, we demonstrated that the transcription factor c-Jun plays a crucial role in the development and progression of this cancer type. 5,11,12 However, the detailed molecular mechanism of c-Jun's influence on melanoma progression and development remains elusive, as only a subset of target genes is known. Previous studies have shown that cancer-relevant genes, such as cyclin D1, p53, and INK4A 25-27 are regulated by c-Jun.…”

Section: Discussionmentioning

confidence: 99%

“…11 Moreover, we identified an alternative regulatory pathway of c-Jun in melanoma cells that leads to an upregulation of c-Jun activity via the loss of the cell-adhesion molecule E-cadherin. 12,13 Although the de-regulation of the transcription factor c-Jun is known to be one of the most important events in the development and progression of malignant melanoma, the specific c-Jun target genes that contribute to the functional effects of c-Jun up-regulation in melanoma cells and their molecular relevance have not been determined.…”

Section: Introductionmentioning

confidence: 99%