New insights into the role of oxidized histone H3 in heterochromatin
Oxidation of histone H3 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) is important in triple-negative breast cancer (TNBC) cells to generate compacted heterochromatin regions. However, the molecular mechanisms by which it establishes chromatin compaction have not yet been characterized. In this thesis, w...
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| Formato: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2019 |
| País: | España |
| Recursos: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/668207 |
| Acesso em linha: | http://hdl.handle.net/10803/668207 |
| Access Level: | acceso abierto |
| Palavra-chave: | Heterochromatin Breast cancer H4K4ox LOXL2 H2A.Z Heterocromatina Càncer de pit 577 |
| Resumo: | Oxidation of histone H3 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) is important in triple-negative breast cancer (TNBC) cells to generate compacted heterochromatin regions. However, the molecular mechanisms by which it establishes chromatin compaction have not yet been characterized. In this thesis, we found that LOXL2 interacts with RUVBL1, RUVBL2, BAF53A, and DMAP1, which are proteins that form complexes involved in the exchange of the histone variant H2A.Z. Genome-wide experiments showed that H2A.Z, RUVBL2, and H3K4ox colocalize in heterochromatin regions in TNBC cells. Moreover, we demonstrated that oxidation of histone H3 is linked to DDB1 recruitment to chromatin and the ubiquitination of H2A through RBX1. Interestingly, the interplay between these series of events is required to maintain H3K4ox-enriched heterochromatin regions. Loss of H3K4ox decreases the levels of H3K9me3 and alters chromatin compaction, thereby compromising the oncogenic properties of TNBC cells. Our data revealed a direct link between H3K4ox maintenance, chromatin compaction, and tumorigenic capacities and suggest novel potential targets for cancer therapy. |
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