Melanoma cell invasiveness is regulated by miR‐211 suppression of the BRN2 transcription factor

Boyle, Glen M.; Woods, Susan L.; Bonazzi, Vanessa; Stark, Mitchell; Hacker, Elke; Aoude, Lauren G.; Dutton‐Regester, Ken; Cook, Anthony; Sturm, Richard A.; Hayward, Nicholas K.

doi:10.1111/j.1755-148x.2011.00849.x

Cited by 159 publications

(185 citation statements)

References 62 publications

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“…5B). Furthermore, it has been shown that MITF regulates TRPM1 gene expression as well as the expression of miR-211-5p, as it resides in the sixth intronic region of TRPM1 (21,22). A significant up-regulation of TRPM1 was confirmed by qPCR (Fig.…”

Section: Braf Inhibition Up-regulates Mir-211-5p Expression Through Mmentioning

confidence: 52%

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Lunavat

Cheng

Einarsdottir

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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The BRAF inhibitors vemurafenib and dabrafenib can be used to treat patients with metastatic melanomas harboring BRAF V600 mutations. Initial antitumoral responses are often seen, but drug-resistant clones with reactivation of the MEK-ERK pathway soon appear. Recently, the secretome of tumor-derived extracellular vesicles (EVs) has been ascribed important functions in cancers. To elucidate the possible functions of EVs in BRAF-mutant melanoma, we determined the RNA content of the EVs, including apoptotic bodies, microvesicles, and exosomes, released from such cancer cells after vemurafenib treatment. We found that vemurafenib significantly increased the total RNA and protein content of the released EVs and caused significant changes in the RNA profiles. RNA sequencing and quantitative PCR show that cells and EVs from vemurafenib-treated cell cultures and tumor tissues harvested from cell-derived and patient-derived xenografts harbor unique miRNAs, especially increased expression of miR-211-5p. Mechanistically, the expression of miR-211-5p as a result of BRAF inhibition was induced by increased expression of MITF that regulates the TRPM1 gene resulting in activation of the survival pathway. In addition, transfection of miR-211 in melanoma cells reduced the sensitivity to vemurafenib treatment, whereas miR-211-5p inhibition in a vemurafenib resistant cell line affected the proliferation negatively. Taken together, our results show that vemurafenib treatment induces miR-211-5p upregulation in melanoma cells both in vitro and in vivo, as well as in subsets of EVs, suggesting that EVs may provide a tool to understand malignant melanoma progression.small RNAs | extracellular vesicles | cancer | noncoding RNAs

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Section: Braf Inhibition Up-regulates Mir-211-5p Expression Through Mmentioning

confidence: 52%

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Lunavat

Cheng

Einarsdottir

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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“…A combination of BRAF, ␤-catenin, and MITF/miR-211 regulates the amount of BRN2 mRNA and protein (10,24,25,56). In this study, we evaluated the significance of posttranslational modification of conserved residues (Thr361 and Ser362) in the BRN2 DBD for cell migration and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Berlin

Denat

Steunou

et al. 2012

Molecular and Cellular Biology

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f MITF-M and PAX3 are proteins central to the establishment and transformation of the melanocyte lineage. They control various cellular mechanisms, including migration and proliferation. BRN2 is a POU domain transcription factor expressed in melanoma cell lines and is involved in proliferation and invasion, at least in part by regulating the expression of MITF-M and PAX3. The T361 and S362 residues of BRN2, both in the POU domain, are conserved throughout the POU protein family and are targets for phosphorylation, but their roles in vivo remain unknown. To examine the role of this phosphorylation, we generated mutant BRN2 in which these two residues were replaced with alanines (BRN2TS¡BRN2AA). When expressed in melanocytes in vitro or in the melanocyte lineage in transgenic mice, BRN2TS induced proliferation and repressed migration, whereas BRN2AA repressed both proliferation and migration. BRN2TS and BRN2AA bound and repressed the MITF-M promoter, whereas PAX3 transcription was induced by BRN2TS but repressed by BRN2AA. Expression of the BRN2AA transgene in a Mitf heterozygous background and in a Pax3 mutant background enhanced the coat color phenotype. Our findings show that melanocyte migration and proliferation are controlled both through the regulation of PAX3 by nonphosphorylated BRN2 and through the regulation of MITF-M by the overall BRN2 level. POU family transcription factors are expressed in a wide variety of cell types. They are involved in diverse functions, such as cell type determination, proliferation, renewal, invasion, and migration. The members of the POU domain family of transcription factors share the POU DNA-binding domain (DBD) called the POU domain. The POU domain consists of two DNA-binding units (POUs for POU specific and POUh for POU homeodomain) connected by a flexible linker (3). This molecular structure allows POU proteins to recognize a large set of DNA targets and also to bind different transactivator proteins, depending on the spacing and the positioning adopted by the two subdomains of the POU DBD (50).POU transcription factor function can be modulated by posttranslational modifications, including sumoylation, oxidation, ubiquitinylation, glycosylation, and particularly phosphorylation (5,20,32). Two residues in the DBD domain, a threonine and a serine, are conserved in all mammalian POU domains (see Table S1 at http://umr3347.curie.fr/fr/quipes-de -recherche/d-veloppement-normal-et-pathologie-des-m-lanocytes /differential-function-non-pho). These serine and/or threonine residues in Oct-1, Pit-1, and BRN2 are phosphorylated by protein kinase A (PKA) (31,46,55).Several lines of evidence suggest that PKA is involved in melanocyte lineage proliferation. Forskolin stimulates the proliferation of human melanocytes (54). Proliferation of human melanocytes is induced in a dose-dependent manner by alphamelanocyte-stimulating hormone (1,57,58). Dibutyryl adenosine cyclic AMP induces the proliferation of epidermal melanocytes in culture (29). PKA phosphorylates claudin-1 and allows its tr...

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“…This represses BRN-2 [9], the transcriptional repressor of PDE5A [3]. Thus hypoxic melanoma microenvironments generate sub-populations of melanocytes with low MITF and PDE5A levels.…”

Section: Article Bodymentioning

confidence: 99%

Melanoma, Viagra, and PDE5 Inhibitors: Proliferation and Metastasis

Houslay

2016

Trends in Cancer

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Melanoma cell invasiveness is regulated by miR‐211 suppression of the BRN2 transcription factor

Cited by 159 publications

References 62 publications

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Melanoma, Viagra, and PDE5 Inhibitors: Proliferation and Metastasis

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Melanoma cell invasiveness is regulated by miR‐211 suppression of the BRN2 transcription factor

Cited by 159 publications

References 62 publications

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

Phosphorylation of BRN2 Modulates Its Interaction with the Pax3 Promoter To Control Melanocyte Migration and Proliferation

Melanoma, Viagra, and PDE5 Inhibitors: Proliferation and Metastasis

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BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

BRAF^V600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells