LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells

被引：40

作者：

Cebria-Costa, J. P. ^{[1
]}

Pascual-Reguant, L. ^{[1
]}

Gonzalez-Perez, A. ^{[2
]}

Serra-Bardenys, G. ^{[1
]}

Querol, J. ^{[1
]}

Cosin, M. ^{[1
]}

Verde, G. ^{[1
,3
]}

Cigliano, R. A. ^{[4
]}

Sanseverino, W. ^{[4
]}

Segura-Bayona, S. ^{[2
]}

Iturbide, A. ^{[5
]}

Andreu, D. ^{[6
]}

Nuciforo, P. ^{[1
]}

Bernado-Morales, C. ^{[1
,7
]}

Rodilla, V. ^{[1
]}

Arribas, J. ^{[1
,7
,8
,9
]}

Yelamos, J. ^{[10
]}

Garcia de Herreros, A. ^{[6
,10
]}

Stracker, T. H. ^{[2
]}

Peiro, S. ^{[1
]}

机构：

[1] Vall dHebron Inst Oncol VHIO, Barcelona 08035, Spain

[2] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Barcelona 08028, Spain

[3] Univ Int Catalunya, Fac Med & Hlth Sci, Barcelona, Spain

[4] Sequentia Biotech SL, Comte Urgell 240, Barcelona, Spain

[5] Helmoholtz Zentrum Munchen, Inst Epigenet & Stem Cells, D-81377 Munich, Germany

[6] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain

[7] Ctr Invest Biomed Red Oncol CIBERONC, Barcelona 08035, Spain

[8] ICREA, Barcelona, Spain

[9] Univ Autonoma Barcelona, Dept Bioquim & Biol Mol, Bellaterra, Spain

[10] Inst Hosp del Mar Invest Med IMIM, Programa Recerca Canc, Barcelona, Spain

来源：

ONCOGENE | 2020年 / 39卷 / 01期

关键词：

OXIDASE-LIKE; 2; DOUBLE-STRAND BREAKS; TO-MESENCHYMAL TRANSITION; DNA-DAMAGE RESPONSE; LYSYL OXIDASE; GENOMIC INSTABILITY; E-CADHERIN; LOXL2; EXPRESSION; TRANSCRIPTION;

D O I：

10.1038/s41388-019-0969-1

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

引用

页码：79 / 121

页数：43

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