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MITF 重编程黑色素瘤中的细胞外基质和焦点黏附。

MITF reprograms the extracellular matrix and focal adhesion in melanoma.

机构信息

Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Department of Anatomy and Cell biology, Carver College of Medicine, University of Iowa, Iowa City, United States.

出版信息

Elife. 2021 Jan 13;10:e63093. doi: 10.7554/eLife.63093.

DOI:10.7554/eLife.63093
PMID:33438577
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7857731/
Abstract

The microphthalmia-associated transcription factor (MITF) is a critical regulator of melanocyte development and differentiation. It also plays an important role in melanoma where it has been described as a molecular rheostat that, depending on activity levels, allows reversible switching between different cellular states. Here, we show that MITF directly represses the expression of genes associated with the extracellular matrix (ECM) and focal adhesion pathways in human melanoma cells as well as of regulators of epithelial-to-mesenchymal transition (EMT) such as CDH2, thus affecting cell morphology and cell-matrix interactions. Importantly, we show that these effects of MITF are reversible, as expected from the rheostat model. The number of focal adhesion points increased upon MITF knockdown, a feature observed in drug-resistant melanomas. Cells lacking MITF are similar to the cells of minimal residual disease observed in both human and zebrafish melanomas. Our results suggest that MITF plays a critical role as a repressor of gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.

摘要

小眼畸形相关转录因子（MITF）是黑素细胞发育和分化的关键调节因子。它在黑色素瘤中也起着重要作用，在黑色素瘤中，它被描述为一个分子变阻器，根据活性水平，允许在不同的细胞状态之间进行可逆切换。在这里，我们表明 MITF 直接抑制人黑色素瘤细胞中与细胞外基质（ECM）和焦点粘连途径相关的基因的表达，以及上皮-间质转化（EMT）的调节剂如 CDH2 的表达，从而影响细胞形态和细胞-基质相互作用。重要的是，我们表明这些 MITF 的作用是可逆的，这与变阻器模型所预期的一致。在 MITF 敲低后，焦点粘连点的数量增加，这是在耐药性黑色素瘤中观察到的特征。缺乏 MITF 的细胞类似于在人类和斑马鱼黑色素瘤中观察到的微小残留疾病的细胞。我们的结果表明，MITF 作为基因表达的抑制剂起着关键作用，并以细胞自主的方式积极参与塑造黑色素瘤细胞的微环境。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/d39ecdfbacba/elife-63093-fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/31b7cca75e6a/elife-63093-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/b0875c77f9e2/elife-63093-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/ca7073c71757/elife-63093-fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/27cef28aab36/elife-63093-fig6-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/d39ecdfbacba/elife-63093-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/bda6a9ac6bab/elife-63093-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/cae1b6b7fbd9/elife-63093-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/7598da91410b/elife-63093-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/4370e8c44a53/elife-63093-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/943c844c1a6b/elife-63093-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/31b7cca75e6a/elife-63093-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/b0875c77f9e2/elife-63093-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/ca7073c71757/elife-63093-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/8cc247e10679/elife-63093-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/021ce6bc801a/elife-63093-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/27cef28aab36/elife-63093-fig6-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a889/7857731/d39ecdfbacba/elife-63093-fig7.jpg

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Genes Dev. 2019 Oct 1;33(19-20):1295-1318. doi: 10.1101/gad.329771.119.
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Peak calling by Sparse Enrichment Analysis for CUT&RUN chromatin profiling.
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