A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITF<sup>high</sup>/AXL<sup>low</sup> melanoma

Smith, Michael P.; Rana, Sareena; Ferguson, Jennifer; Rowling, Emily J.; Flaherty, Keith T.; Wargo, Jennifer A.; Marais, Richard; Wellbrock, Claudia

doi:10.1111/pcmr.12741

Cited by 32 publications

(24 citation statements)

References 42 publications

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“…1a). PAX3, a transcription factor recently shown to function in a rheostat model with BRN2 to control MITF expression, was detected in all three cell lines 21 irrespective of MITF level (Fig. 1a).…”

Section: Brn2 Expression Reduces Cell Proliferationmentioning

confidence: 86%

BRN2 expression increases anoikis resistance in melanoma

et al. 2020

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Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole-genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2-expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2-expressing cells under non-adherent conditions to death by anoikis. Alternative inhibitors of c-MET showed similar results. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2-expressing cells resistant to therapy and cell death by anoikis.

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Section: Brn2 Expression Reduces Cell Proliferationmentioning

confidence: 86%

BRN2 expression increases anoikis resistance in melanoma

et al. 2020

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“…It has to be noted that some other transcriptional factors are also involved in MITF activation in the formation of BRAFi resistance in melanoma. Paired box 3 (PAX3) is a classic transcriptional inducer of MITF and is necessary for the up-regulation of MITF induced by BRAF/MEK inhibition 42 . Cadherin-associated protein beta 1 (β-catenin) is another known transcription factor that regulates the expression of MITF 43 .…”

Section: Discussionmentioning

confidence: 99%

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

Liu

Qiao

et al. 2020

Cell Death Dis

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BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in the treatment of melanoma with BRAF mutation. Nevertheless, most patients end up with the development of BRAFi resistance, which strongly limits the clinical application of these agents. POU4F1 is a stem cell-associated transcriptional factor that is highly expressed in melanoma cells and contributes to BRAF-activated malignant transformation. However, whether POU4F1 contributes to the resistance of melanoma to BRAFi remains poorly understood. Here, we report that over-expressed POU4F1 contributed to the acquired resistance of melanoma cells to Vemurafenib. Furthermore, POU4F1 promoted the activation of ERK signaling pathway via transcriptional regulation on MEK expression. In addition, POU4F1 could increase the expression of MITF to retain the resistance of melanoma cells to BRAFi. Collectively, our findings reveal that POU4F1 reactivates the MAPK pathway by transcriptional regulation on MEK expression and promotes MITF expression, which ultimately results in the resistance to BRAFi in melanoma. Our study supports that POU4F1 is a potential combined therapeutic target with BRAFi therapy for melanoma.

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“…We demonstrated that downregulation of MITF is the consequence of a known pathway, in which MAPK activation phosphorylates the transcription factor and targets it to degradation [27]. In contrast, UM-164 inhibited ERK and caused activation of MITF, an effect that may reduce the long term impact on cell proliferation and contribute to the development of drug resistance as described for BRAF- and MEK inhibitors [28]. Analysis of biopsies from BRAF V600E melanoma patients following relapse with vemurafenib, or combination of dabrafenib and trametinib revealed upregulation of several lineage-specific transcription factors including MITF [29].…”

Section: Discussionmentioning

confidence: 99%

A novel anti-melanoma SRC-family kinase inhibitor

et al. 2019

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The major drawback of melanoma therapy with BRAF and MAPK inhibitors is the innate and acquired drug resistance. We therefore explored alternative targets and developed a new compound, SAB298, that is a SRC-family kinase (SFK) inhibitor. The drug is cytotoxic to patient-derived melanoma cells regardless of oncogene expression and inhibits tumor growth in vivo . As expected, it inhibited SRC and PI3K activity, and had the additional property of ERBB2 inhibition, that lead to inactivation of the two ERK phosphatases PP2A and SHP2. In 57% of the melanoma cell lines tested, the consequent increase in ERK activity lead to proteolytic degradation of its substrate, the lineage specific transcription factor MITF, likely contributing to growth arrest. Treatment with a combination of SAB298 and AZD6244 (selumetinib), induced a synergistic growth inhibition, suggesting that the new compound could be used in the clinic as a substitute for, or in combination with MAPK inhibitors.

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A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITF^high/AXL^low melanoma

Cited by 32 publications

References 42 publications

BRN2 expression increases anoikis resistance in melanoma

BRN2 expression increases anoikis resistance in melanoma

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

A novel anti-melanoma SRC-family kinase inhibitor

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A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITFhigh/AXLlow melanoma

Cited by 32 publications

References 42 publications

BRN2 expression increases anoikis resistance in melanoma

BRN2 expression increases anoikis resistance in melanoma

POU4F1 promotes the resistance of melanoma to BRAF inhibitors through MEK/ERK pathway activation and MITF up-regulation

A novel anti-melanoma SRC-family kinase inhibitor

Contact Info

Product

Resources

About

A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITF^high/AXL^low melanoma