Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene.
Life Sci Alliance
; 4(8)2021 08.
Article
em En
| MEDLINE
| ID: mdl-34187875
ABSTRACT
The oncogenic role of common fragile sites (CFS), focal and pervasive gaps in the cancer genome arising from replicative stress, remains controversial. Exploiting the TCGA dataset, we found that in most CFS the genes residing within the associated focal deletions are down-regulated, including proteins involved in tumour immune recognition. In a subset of CFS, however, the residing genes are surprisingly overexpressed. Within the most frequent CFS in this group, FRA4F, which is deleted in up to 18% of cancer cases and harbours the CCSER1 gene, we identified a region which includes an intronic, antisense pseudogene, TMSB4XP8. TMSB4XP8 focal ablation or transcriptional silencing elicits the overexpression of CCSER1, through a cis-acting mechanism. CCSER1 overexpression increases proliferation and triggers centrosome amplifications, multinuclearity, and aberrant mitoses. Accordingly, FRA4F is associated in patient samples to mitotic genes deregulation and genomic instability. As a result, cells overexpressing CCSER1 become sensitive to the treatment with aurora kinase inhibitors. Our findings point to a novel tumourigenic mechanism where focal deletions increase the expression of a new class of "dormant" oncogenes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Regulação para Cima
/
Deleção de Genes
/
Proteínas de Ciclo Celular
/
Sítios Frágeis do Cromossomo
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Life Sci Alliance
Ano de publicação:
2021
Tipo de documento:
Article