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SET结构域蛋白6（SETD6）介导黑素瘤细胞中BRD4与小眼畸形相关转录因子（MITF）的选择性相互作用及基因组占位。

SETD6 mediates selective interaction and genomic occupancy of BRD4 and MITF in melanoma cells.

作者信息

Biton Tzofit Elbaz, Feldman Michal, Davidy Tomer, Moskovitz Nili Tickotsky, Levin Liron, Sevilla Daniel, Goding Colin R, Bernstein Emily, Levy Dan

机构信息

The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, P.O.B. 653, Be'er-Sheva 84105, Israel.

National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er-Sheva 84105, Israel.

出版信息

NAR Cancer. 2025 Aug 7;7(3):zcaf023. doi: 10.1093/narcan/zcaf023. eCollection 2025 Sep.

DOI:10.1093/narcan/zcaf023
PMID:40809945
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12342177/
Abstract

Aberrant transcriptional programs mediate malignant transformation of melanoma, the most aggressive form of skin cancer. The lysine methyltransferase SETD6 has been implicated in regulating transcription, cell adhesion, migration, and other processes in various cancers; however its role in melanoma remains unexplored. We recently reported that SETD6 monomethylates the BRD4 at K99 to selectively regulate transcription of genes involved in mRNA (messenger RNA) translation. Here, we observed that BRD4 methylation at K99 by SETD6 occurs in melanoma cells. Knockout of SETD6 or a point mutation at BRD4-K99 disrupts BRD4 genomic occupancy. In addition, we show that SETD6 interacts with MITF, a master transcription factor in melanocytes and melanoma, and influences the genomic distribution of MITF. Mechanistically, we uncover a novel chromatin-localized interaction between BRD4 and MITF in melanoma. Our data suggest that BRD4 binds MITF in melanoma cells and that this interaction is dependent on both SETD6-mediated methylation of BRD4 and MITF acetylation. This chromatin complex plays a pivotal role in selective recruitment of BRD4 and MITF to different genomic loci in melanoma cells.

摘要

异常的转录程序介导黑色素瘤（最具侵袭性的皮肤癌形式）的恶性转化。赖氨酸甲基转移酶SETD6参与调节多种癌症中的转录、细胞黏附、迁移及其他过程；然而其在黑色素瘤中的作用仍未被探索。我们最近报道，SETD6使BRD4在K99位点发生单甲基化，以选择性调节参与信使核糖核酸（mRNA）翻译的基因转录。在此，我们观察到SETD6介导的BRD4在K99位点的甲基化发生在黑色素瘤细胞中。敲除SETD6或BRD4-K99位点的点突变会破坏BRD4在基因组中的占位。此外，我们发现SETD6与MITF（黑素细胞和黑色素瘤中的主要转录因子）相互作用，并影响MITF的基因组分布。从机制上讲，我们揭示了黑色素瘤中BRD4与MITF之间一种新的染色质定位相互作用。我们的数据表明，BRD4在黑色素瘤细胞中与MITF结合，且这种相互作用依赖于SETD6介导的BRD4甲基化和MITF乙酰化。这种染色质复合物在黑色素瘤细胞中BRD4和MITF选择性募集到不同基因组位点的过程中起关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/a6847e5387bb/zcaf023fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/e8a4158eab7e/zcaf023figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/b699439af7e2/zcaf023fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/26ba31baea67/zcaf023fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/8f518ecba10c/zcaf023fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/6193e93ceaa6/zcaf023fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/bd45cbf3fb6e/zcaf023fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/e7e3fa76a467/zcaf023fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/a4dcaaadeb9b/zcaf023fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/a6847e5387bb/zcaf023fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/e8a4158eab7e/zcaf023figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/b699439af7e2/zcaf023fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/26ba31baea67/zcaf023fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/8f518ecba10c/zcaf023fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/6193e93ceaa6/zcaf023fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/bd45cbf3fb6e/zcaf023fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/e7e3fa76a467/zcaf023fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/a4dcaaadeb9b/zcaf023fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80a6/12342177/a6847e5387bb/zcaf023fig8.jpg

相似文献

[1]
SETD6 mediates selective interaction and genomic occupancy of BRD4 and MITF in melanoma cells.

NAR Cancer. 2025-8-7

[2]
RAD18 methylation by the methyltransferase SETD6 attenuates DNA breaks.

Sci Rep. 2025-8-27

[3]
BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.

Sci Adv. 2021-5

[4]
EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression.

Br J Cancer. 2025-6-4

[5]
TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes.

PLoS Genet. 2022-5

[6]
Application and mechanisms of targeting BRD4 in osteosarcoma.

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025-3-28

[7]
A heterodimer of hemoglobin identifies theranostic targets on brain-metastasizing melanoma cells.

Int J Cancer. 2025-8-15

[8]
BRD4 silencing attenuates hemin-induced neuronal ferroptosis and inflammation via the H3K27ac-ATF3 axis in an in vitro model of cerebral hemorrhage.

Eur J Med Res. 2025-7-2

[9]
BRD4 acts as a transcriptional repressor of RhoB to inhibit terminal erythropoiesis.

J Hematol Oncol. 2025-7-1

[10]
SOX10, MITF, and microRNAs: Decoding their interplay in regulating melanoma plasticity.

Int J Cancer. 2025-10-1

本文引用的文献

[1]
Super-enhancer Activates Master Transcription Factor NR3C1 Expression and Promotes 5-FU Resistance in Gastric Cancer.

Adv Sci (Weinh). 2025-2

[2]
Acetylation reprograms MITF target selectivity and residence time.

Nat Commun. 2023-9-28

[3]
Methylation of the transcription factor E2F1 by SETD6 regulates SETD6 expression via a positive feedback mechanism.

J Biol Chem. 2023-10

[4]
Exploring Epigenomic Datasets by ChIPseeker.

Curr Protoc. 2022-10

[5]
TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in glioma.

Nucleic Acids Res. 2022-7-8

[6]
Structure-function conservation between the methyltransferases SETD3 and SETD6.

Biochimie. 2022-9

[7]
BRD4 methylation by the methyltransferase SETD6 regulates selective transcription to control mRNA translation.

Sci Adv. 2021-5

[8]
Biophysical characterization of melanoma cell phenotype markers during metastatic progression.

Eur Biophys J. 2021-5

[9]
Twelve years of SAMtools and BCFtools.

Gigascience. 2021-2-16

[10]
circNR3C1 Suppresses Bladder Cancer Progression through Acting as an Endogenous Blocker of BRD4/C-myc Complex.

Mol Ther Nucleic Acids. 2020-9-16

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