A POU3F2-MITF-SHC4 Axis in Phenotype Switching of Melanoma Cells

Strub, Thomas; Kobi, Dominique; Koludrović, Dana; Davidson, Irwin

doi:10.5772/19769

Cited by 6 publications

(6 citation statements)

References 73 publications

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“…Alterations of the FGFR1 gene, a tyrosine-kinase receptor (RTK), have been described in many tumors [ 23 , 24 ]. Other candidate genes are known to be involved in oncogenic RTK pathways, such as SHC4 [ 25 ] and ST5/DENND2B [ 26 ]. The CEP131 gene is involved in cell proliferation and migration through the activation of the phosphoinositide 3-kinase (PI3K/Akt) signaling [ 27 ] and the SMAD3 gene is a key mediator of the transforming growth factor-β (TGF-β) signaling pathway involved in cancer progression [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

2018

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Devil Facial Tumor Disease (DFTD) is an aggressive cancer notorious for its rare etiology and its impact on Tasmanian devil populations. Two regions underlying an evolutionary response to this cancer were recently identified using genomic time-series pre- and post-DTFD arrival. Here, we support that DFTD shaped the genome of the Tasmanian devil in an even more extensive way than previously reported. We detected 97 signatures of selection, including 148 protein coding genes having a human orthologue, linked to DFTD. Most candidate genes are associated with cancer progression, and an important subset of candidate genes has additional influence on social behavior. This confirms the influence of cancer on the ecology and evolution of the Tasmanian devil. Our work also demonstrates the possibility to detect highly polygenic footprints of short-term selection in very small populations.

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Section: Resultsmentioning

confidence: 99%

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

2018

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“…This latter interpretation could be related to the mechanisms involved in phenotype switching of melanoma cells, where melanoma cells are induced to de-differentiate from a relatively strongly differentiated and proliferative melanoma cell lineage to a more stem cell-like phenotype with reduced proliferation and enhanced cell migration (10, 17, 29). …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, POU3F2 both transcriptionally activates (including transactivation of PAX3 ) and represses genes leading to enhanced cell migration/invasion and stem cell-like characteristics (15–20). Indeed, POU3F2 is part of the phosphatidylinositol 3-kinase (PI3K)-PAX3-POU3F2 (BRN2) axis that has been proposed to promote melanoma cell invasion (21).…”

Section: Introductionmentioning

confidence: 99%

MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a “Genetic Switch” Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma

Eccles

Ahn

et al. 2013

Front. Oncol.

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Melanoma is a very aggressive neoplasm with a propensity to undergo progression and invasion early in its evolution. The molecular pathways underpinning invasion in melanoma are now just beginning to be elucidated, but a clear understanding of the transition from non-invasive to invasive melanoma cells remains elusive. Microphthalmia-associated transcription factor (MITF), is thought to be a central player in melanoma biology, and it controls many aspects of the phenotypic expression of the melanocytic lineage. However, recently the paired box transcription factor PAX3 was shown to transcriptionally activate POU3F2/BRN2, leading to direct repression of MITF expression. Here we present a theory to explain melanoma phenotype switching and discuss the predictions that this theory makes. One prediction is that independent and opposing roles for MITF and PAX3 in melanoma would be expected, and we present empirical evidence supporting this: in melanoma tissues PAX3 expression occurs independently of MITF, and PAX3 does not play a key role in melanoma cell proliferation. Furthermore, we show that knockdown of PAX3 inhibits cell migration in a group of “lower MITF” melanoma cell lines, while knockdown of MITF promotes cell migration in a complementary “higher MITF” group of melanoma cell lines. Moreover, the morphological effects of knocking down PAX3 versus MITF in melanoma cells were found to differ. While these data support the notion of independent roles for MITF and PAX3, additional experiments are required to provide robust examination of the proposed genetic switch theory. Only upon clear delineation of the mechanisms associated with progression and invasion of melanoma cells will successful treatments for invasive melanoma be developed.

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“…An MITF Low state is also associated with drug-resistance (Dugo et al, 2015;Konieczkowski et al, 2014;Muller et al, 2014;Rambow et al, 2018), and tumor-initiation capacity (Cheli et al, 2011). MITF presumably represses genes implicated in invasion (Strub et al, 2011), and activates those necessary for proliferation, a high nutrient-demand state. However, although MITF has been identified as a key regulator of mitobiogenesis via its regulation of Peroxisome Proliferatoractivated Receptor Gamma Co-activator 1-alpha (PGC1PPARGC1A (Haq et al, 2013;Vazquez et al, 2013) and controls the TCA cycle by regulating SDHB (Louphrasitthiphol et al, 2019), whether MITF regulates additional genes implicated in the metabolic rewiring that differentiates proliferative and invasive cells is not known.…”

Section: Introductionmentioning

confidence: 99%

Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity

et al. 2020

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Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITF High melanoma cell proliferation. By contrast MITF Low cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.

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A POU3F2-MITF-SHC4 Axis in Phenotype Switching of Melanoma Cells

Cited by 6 publications

References 73 publications

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a “Genetic Switch” Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma

Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity

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