MITF-the first 25 years Goding, Colin R; Arnheiter, Heinz
Genes & development,
08/2019, Volume:
33, Issue:
15-16
Journal Article
Peer reviewed
Open access
All transcription factors are equal, but some are more equal than others. In the 25 yr since the gene encoding the microphthalmia-associated transcription factor (MITF) was first isolated, MITF has ...emerged as a key coordinator of many aspects of melanocyte and melanoma biology. Like all transcription factors, MITF binds to specific DNA sequences and up-regulates or down-regulates its target genes. What marks MITF as being remarkable among its peers is the sheer range of biological processes that it appears to coordinate. These include cell survival, differentiation, proliferation, invasion, senescence, metabolism, and DNA damage repair. In this article we present our current understanding of MITF's role and regulation in development and disease, as well as those of the MITF-related factors TFEB and TFE3, and highlight key areas where our knowledge of MITF regulation and function is limited.
An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics. ...Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies. Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.
In a recent study, Leucci et al. report a role for the long non-coding RNA SAMMSON in driving mitochondrial function in melanoma. Targeting SAMMSON, the gene of which is frequently co-amplified with ...MITF, highlights a new cell-type-specific therapeutic vulnerability in melanoma irrespective of BRAF, NRAS, or p53 status.
In a recent study, Leucci et al. report a role for the long non-coding RNA SAMMSON in driving mitochondrial function in melanoma. Targeting SAMMSON, the gene of which is frequently co-amplified with MITF, highlights a new cell-type-specific therapeutic vulnerability in melanoma irrespective of BRAF, NRAS, or p53 status.
The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; ...however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAFV600E, MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes’ response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.
•UVB exposure triggers PTEN interaction with wild-type, but not MC1R RHC variants•WT, but not MC1R RHC variants, protect PTEN from WWP2-mediated ubiquitination•MC1R deficiency leads to the onset of premature senescence in primary melanocytes•MC1R deficiency cooperates with BRAFV600E to drive melanomagenesis
Summary
Tumours comprise multiple phenotypically distinct subpopulations of cells, some of which are proposed to possess stem cell‐like properties, being able to self‐renew, seed and maintain ...tumours, and provide a reservoir of therapeutically resistant cells. Here, we use melanoma as a model to explore the validity of the cancer stem cell hypothesis in the light of accumulating evidence that melanoma progression may instead be driven by phenotype‐switching triggered by genetic lesions that impose an increased sensitivity to changes in the tumour microenvironment. Although at any given moment cells within a tumour may exhibit differentiated, proliferative or invasive phenotypes, an ability to switch phenotypes implies that most cells will have the potential to adopt a stem cell‐like identity. Insights into the molecular events underpinning phenotype‐switching in melanoma highlight the close relationship between signalling pathways that generate, maintain and activate melanocyte stem cells as well as the inverse correlation between proliferation and invasive potentials. An understanding of phenotype‐switching in melanoma, and in particular the signalling events that regulate the expression of the microphthalmia‐associated transcription factor Mitf, points to new therapeutic opportunities aimed at eradicating therapeutically resistant stem cell‐like melanoma cells.
Considerable progress has been made in identifying microenvironmental signals that effect the reversible phenotypic transitions underpinning the early steps in the metastatic cascade. However, ...although the general principles underlying metastatic dissemination have been broadly outlined, a common theme that unifies many of the triggers of invasive behavior in tumors has yet to emerge. Here we discuss how many diverse signals that induce invasion converge on the reprogramming of protein translation via phosphorylation of eIF2α, a hallmark of the starvation response. These include starvation as a consequence of nutrient or oxygen limitation, or pseudo-starvation imposed by cell-extrinsic microenvironmental signals or by cell-intrinsic events, including oncogene activation. Since in response to resource limitation single-cell organisms undergo phenotypic transitions remarkably similar to those observed within tumors, we propose that a starvation/pseudo-starvation model to explain cancer progression provides an integrated and evolutionarily conserved conceptual framework to understand the progression of this complex disease.
García-Jiménez and Goding discuss how many of the triggers of invasion in cancer converge on translation reprogramming, a hallmark of the starvation response. They propose that cancer invasion reflects an evolutionarily conserved adaptation to nutrient limitation in which the starvation response has been hijacked by microenvironmental signals, including inflammation.
The ability of stem cells to self-renew and generate different lineages during development and organogenesis is a fundamental, tightly controlled, and generally unidirectional process, whereas the ...'immortality' of cancer cells could be regarded as pathological self-renewal. The molecular mechanisms that underpin the generation of induced pluripotent stem cells are remarkably similar to those that are deregulated in cancer - so much so that aberrant reprogramming is tumorigenic. The similarities also suggest that mutations in genes implicated in DNA methylation dynamics might represent a hallmark of cancers with a stem cell origin, and they highlight an alternative view of cancer that may be of clinical benefit.
How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes ...de-phosphorylation and nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3β phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized nuclear export signal (NES). Importantly, GSK3β is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a nuclear import-export cycle.
Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is ...associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.
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