<br>需要 LOXL2 介导的染色质压缩来维持三阴性乳腺癌细胞的致癌特性,The FEBS Journal

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需要 LOXL2 介导的染色质压缩来维持三阴性乳腺癌细胞的致癌特性
The FEBS Journal ( IF 5.5 ) Pub Date : 2024-03-07 , DOI: 10.1111/febs.17112
Gemma Serra-Bardenys _{1,

2} , Enrique Blanco ₃ , Carmen Escudero-Iriarte ₁ , Queralt Serra-Camprubí ₁ , Jessica Querol ₁ , Laura Pascual-Reguant ₃ , Beatriz Morancho ₁ , Marta Escorihuela ₁ , Natalia Soledad Tissera ₁ , Anna Sabé ₁ , Luna Martín ₁ , Sandra Segura-Bayona ₄ , Gaetano Verde ₁ , Riccardo Aiese Cigliano ₅ , Alba Millanes-Romero ₆ , Celia Jerónimo _{3,

7} , Joan Pau Cebrià-Costa ₁ , Paolo Nuciforo ₁ , Sara Simonetti ₁ , Cristina Viaplana ₁ , Rodrigo Dienstmann ₁ , Mafalda Oliveira _{1,

8} , Vicente Peg _{8,

9,

10,

11} , Travis H Stracker ₁₂ , Joaquín Arribas _{1,

10,

13,

14} , Francesc Canals ₁ , Josep Villanueva ₁ , Luciano Di Croce _{3,

13} , Antonio García de Herreros _{14,

15} , Tian V Tian ₁ , Sandra Peiró ₁

Affiliation

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Institut Bonanova FP Sanitaria, Consorci Mar Parc de Salut de Barcelona, Spain.
Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Spain.
The Francis Crick Institute, London, UK.
Sequentia Biotech SL, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona) and Barcelona Institute of Science and Technology, Spain.
Institut de Recherches Cliniques de Montréal, Canada.
Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
Centro de Investigación Biomédica en Red en Oncología (CIBERONC), Barcelona, Spain.
Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.

组蛋白 H3 在赖氨酸 4 （H3K4ox）位点的氧化由赖氨酰氧化酶同源物 2 （LOXL2）催化。这种组蛋白修饰在三阴性乳腺癌（TNBC）细胞的异染色质中富集，并与紧密染色质的维持有关。然而，这种维持的分子机制仍然未知。在这里，我们表明 LOXL2 与 RuvB 样蛋白 1 （RUVBL1）、RuvB 样蛋白 2 （RUVBL2）、肌动蛋白样蛋白 6A （ACTL6A）和 DNA 甲基转移酶 1 相关蛋白 1 （DMAP1）相互作用，DMAP1 是一种参与组蛋白变体 H2AZ 掺入的复合物。我们的实验表明，这种相互作用和 RUVBL2 的活性形式是维持 LOXL2 依赖性染色质压缩所必需的。全基因组实验表明，H2A.Z、RUVBL2 和 H3K4ox 共定位于异染色质区域。在不存在 LOXL2 或 RUVBL2 的情况下，异染色质组蛋白标记 H3K9me3 的整体水平强烈降低，H3K9me3 区域的 ATAC-seq 信号增加。最后，我们观察到这一系列事件之间的相互作用是维持富含 H3K4ox 的异染色质区域所必需的，这反过来又是维持测试的 TNBC 细胞系（MDA-MB-231）致癌特性的关键。

"点击查看英文标题和摘要"

LOXL2‐mediated chromatin compaction is required to maintain the oncogenic properties of triple‐negative breast cancer cells

Oxidation of histone H3 at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase homolog 2 (LOXL2). This histone modification is enriched in heterochromatin in triple‐negative breast cancer (TNBC) cells and has been linked to the maintenance of compacted chromatin. However, the molecular mechanism underlying this maintenance is still unknown. Here, we show that LOXL2 interacts with RuvB‐Like 1 (RUVBL1), RuvB‐Like 2 (RUVBL2), Actin‐like protein 6A (ACTL6A), and DNA methyltransferase 1associated protein 1 (DMAP1), a complex involved in the incorporation of the histone variant H2A.Z. Our experiments indicate that this interaction and the active form of RUVBL2 are required to maintain LOXL2‐dependent chromatin compaction. Genome‐wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions. In the absence of LOXL2 or RUVBL2, global levels of the heterochromatin histone mark H3K9me3 were strongly reduced, and the ATAC‐seq signal in the H3K9me3 regions was increased. Finally, we observed that the interplay between these series of events is required to maintain H3K4ox‐enriched heterochromatin regions, which in turn is key for maintaining the oncogenic properties of the TNBC cell line tested (MDA‐MB‐231).

更新日期：2024-03-07

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