The MITF regulatory network in melanoma

Bidirectional interactions between plastic tumor cells and the microenvironment critically impact tumor evolution and metastatic dissemination by enabling cancer cells to adapt to microenvironmental stresses by switching phenotype. In melanoma, a key determinant of phenotypic identity is the microph...

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Bibliographic Details
Published in:Pigment cell and melanoma research Vol. 35; no. 5; pp. 517 - 533
Main Authors: Chauhan, Jagat S., Hölzel, Michael, Lambert, Jean‐Philippe, Buffa, Francesca M., Goding, Colin R.
Format: Journal Article
Language:English
Published: England Wiley Subscription Services, Inc 01.09.2022
Subjects:
Activating transcription factor 3
Activator protein 1
Animals
beta Catenin - metabolism
beta‐catenin
Catenin
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Genes
Humans
Infiltration
Invasiveness
Melanoma
Melanoma - pathology
Metastases
Mice
Microenvironments
Microphthalmia-associated transcription factor
Microphthalmia-Associated Transcription Factor - genetics
Microphthalmia-Associated Transcription Factor - metabolism
MITF
notch
Phenotypes
Senescence
Signal Transduction
Signaling
Transcription factors
Tumor cells
tumor immune infiltration
Tumor Microenvironment
Tumors
beta-catenin
tumor immune infiltration
melanoma
MITF
notch
ISSN:1755-1471, 1755-148X, 1755-148X
Online Access:Get full text
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Summary:Bidirectional interactions between plastic tumor cells and the microenvironment critically impact tumor evolution and metastatic dissemination by enabling cancer cells to adapt to microenvironmental stresses by switching phenotype. In melanoma, a key determinant of phenotypic identity is the microphthalmia‐associated transcription factor MITF that promotes proliferation, suppresses senescence, and anticorrelates with immune infiltration and therapy resistance. What determines whether MITF can activate or repress genes associated with specific phenotypes, or how signaling regulating MITF might impact immune infiltration is poorly understood. Here, we find that MITF binding to genes associated with high MITF is via classical E/M‐box motifs, but genes downregulated when MITF is high contain FOS/JUN/AP1/ATF3 sites. Significantly, the repertoire of MITF‐interacting factors identified here includes JUN and ATF3 as well as many previously unidentified interactors. As high AP1 activity is a hallmark of MITFLow, invasive, slow‐cycling, therapy resistant cells, the ability of MITF to repress AP1‐regulated genes provides an insight into how MITF establishes and maintains a pro‐proliferative phenotype. Moreover, although β‐catenin has been linked to immune exclusion, many Hallmark β‐catenin signaling genes are associated with immune infiltration. Instead, low MITF together with Notch signaling is linked to immune infiltration in both mouse and human melanoma tumors.
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ISSN:1755-1471
1755-148X
1755-148X
DOI:10.1111/pcmr.13053