Brn-2 Represses Microphthalmia-Associated Transcription Factor Expression and Marks a Distinct Subpopulation of Microphthalmia-Associated Transcription Factor–Negative Melanoma Cells

Goodall, Jane; Carreira, Suzanne; Denat, Laurence; Kobi, Dominique; Davidson, Irwin; Nuciforo, Paolo; Sturm, Richard A.; Larue, Lionel; Goding, Colin R.

doi:10.1158/0008-5472.can-08-1053

Cited by 177 publications

(303 citation statements)

References 26 publications

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“…Interestingly, BRN-2 (POU3F2), which belongs with Oct4 (POU5F1) to the POU domain transcription factor family, functions at the cross road between ERK and WNT pathways. BRN-2 identifies in some melanoma, a population of Mitf negative cells with increased invasive properties (Goodall et al, 2008). Intravital imaging study revealed a reversible switching between poorly differentiated, BRN-2-high and highly pigmented BRN-2-low melanoma cells (Pinner et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

et al. 2011

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In melanoma, as well as in other solid tumors, the cells within a given tumor exhibit strong morphological, functional and molecular heterogeneity that might reflect the existence of different cancer cell populations, among which are melanoma-initiating cells (MICs) with 'stemness' properties and their differentiated, fast-growing progeny. The existence of a slow-growing population might explain the resistance of melanoma to classical chemotherapies that target fast growing cells. Therefore, elucidating the biologic properties of MICs and, more importantly, the molecular mechanisms that drive the transition between MICs and their proliferating progeny needs to be addressed to develop an efficient melanoma therapy. Using B16 mouse melanoma cells and syngeneic mice, we show that the inhibition of microphthalmiaassociated transcription factor (Mitf), the master regulator of melanocyte differentiation, increases the tumorigenic potential of melanoma cells and upregulates the stem cell markers Oct4 and Nanog. Notably, p27, the CDK inhibitor, is increased in Mitf-depleted cells and is required for exacerbation of the tumorigenic properties of melanoma cells. Further, a slow-growing population with low-Mitf level and high tumorigenic potential exists spontaneously in melanoma. Ablation of this population dramatically decreases tumor formation. Importantly, these data were confirmed using human melanoma cell lines and freshly isolated human melanoma cell from lymph node and skin melanoma metastasis. Taken together our data, identified Mitf and p27 as the key molecular switches that control the transition between MICs and their differentiated progeny. Eradication of low-Mitf cells might be an appealing strategy to cure melanoma.

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Section: Discussionmentioning

confidence: 99%

Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

et al. 2011

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“…This pathway is also involved in the regulation of melanin synthesis. It has been reported that activation of MEK/ERK leads to phosphorylation of MITF at serine 73, resulting in its degradation [28,38] . The PI3K⁄Akt pathway plays an important role in cell growth regulation and apoptosis inhibition [39,40] .…”

Section: Discussionmentioning

confidence: 99%

[6]-Shogaol inhibits melanogenesis in B16 mouse melanoma cells through activation of the ERK pathway

Cheng

et al. 2012

Acta Pharmacol Sin

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Aim:To investigate the effect of [6]-shogaol, an active ingredient in ginger, on melanogenesis and the underlying mechanisms. Methods: B16F10 mouse melanoma cells were tested. Cell viability was determined with the MTT assay. Melanin content and tyrosinase activity were analyzed with a spectrophotometer. The protein expression of tyrosinase and microphthalmia associated transcription factor (MITF), as well as phosphorylated or total ERK1/2 and Akt were measured using Western blot.

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“…In this context, mTOR inhibition has also been shown to suppress the outgrowth of clones with resistance to MAPK inhibition 126 . Finally, in those melanomas in which MITF expression is not restored 132 , many receptor tyrosine kinases can be upregulated and contribute to the resistant phenotype 133,134 (FIG. 4a).…”

Section: Braf-mek-inhibitor Resistance and Biomarkersmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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Brn-2 Represses Microphthalmia-Associated Transcription Factor Expression and Marks a Distinct Subpopulation of Microphthalmia-Associated Transcription Factor–Negative Melanoma Cells

Cited by 177 publications

References 26 publications

Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny

[6]-Shogaol inhibits melanogenesis in B16 mouse melanoma cells through activation of the ERK pathway

Targeted agents and immunotherapies: optimizing outcomes in melanoma

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