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LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells
- Source :
- Oncogene 39, 79-121 (2020), Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Oncogene, Scientia
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- Cromosomes; Marcadors pronòstics Cromosomas; Marcadores de pronóstico Chromosomes; Prognostic markers 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. This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI12/01250; CP08/00223; PI16/00253; and CB16/12/00449), MINECO (SAF2013-48849-C2-1-R) to SP, BFU2015-68354 to THS, Breast Cancer Research Foundation (BCRF-17-008) to JA, AGL2014-52395-C2-2-R to DA, Worldwide Cancer Research, Red Temática de Investigación Cooperativa en Cáncer (RD012/0036/005), Fundación Científica de la Asociación Española contra el Cáncer, and Fundació La Marató TV3. THS was supported by institutional funding (MINECO) through the Centres of Excellence Severo Ochoa award and the CERCA Programme of the Catalan Government, and SS-B, by a Fundació La Caixa fellowship. We thank La Caixa Foundation and Cellex Foundation for provide research facilities and equipment. GV has received funding from the MINECO (a “Juan de la Cierva Incorporation” fellowship; IJCI-2014-20723). SP was a recipient of a Miguel Servet contract (ISCIII/FIS), and AI, JPC-C, LP-G, and GS-B are supported by contracts from Worldwide Cancer Research, Fundació La Marató TV3, Fundació FERO, and a FI Fellowship from the Generalitat de Catalunya, respectively.
- Subjects :
- 0301 basic medicine
Mama -- Càncer -- Aspectes genètics
Cancer Research
Triple Negative Breast Neoplasms
fenómenos genéticos::regulación de la expresión génica::regulación de la expresión génica neoplásica [FENÓMENOS Y PROCESOS]
Cromatina
Histones
Mice
Prognostic markers
0302 clinical medicine
Heterochromatin
Triple-negative breast cancer
Regulation of gene expression
LOXL2
fenómenos genéticos::estructuras genéticas::estructuras cromosómicas::cromatina [FENÓMENOS Y PROCESOS]
Chromatin
Gene Expression Regulation, Neoplastic
Histone Code
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES]
Heterografts
Female
Amino Acid Oxidoreductases
Oxidation-Reduction
Genetic Phenomena::Genetic Structures::Chromosome Structures::Chromatin [PHENOMENA AND PROCESSES]
DNA damage
Genetic Phenomena::Gene Expression Regulation::Gene Expression Regulation, Neoplastic [PHENOMENA AND PROCESSES]
Mama -- Càncer -- Tractament
Biology
Article
Chromosomes
03 medical and health sciences
Breast cancer
Cell Line, Tumor
Regulació genètica
Genetics
medicine
Animals
Humans
Molecular Biology
Lysine
medicine.disease
neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES]
030104 developmental biology
Cell culture
Cancer research
Mama - Càncer - Aspectes genètics
DNA Damage
Subjects
Details
- Language :
- German
- Database :
- OpenAIRE
- Journal :
- Oncogene 39, 79-121 (2020), Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona, Oncogene, Scientia
- Accession number :
- edsair.doi.dedup.....daabe112cd5499be77ca94ee16d69ec5