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.

Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene / Santoliquido, B. M.; Frenquelli, M.; Contadini, C.; Bestetti, S.; Gaviraghi, M.; Barbieri, E.; de Antoni, A.; Albarello, L.; Amabile, A.; Gardini, A.; Lombardo, A.; Doglioni, C.; Provero, P.; Soddu, S.; Cittaro, D.; Tonon, G.. - In: LIFE SCIENCE ALLIANCE. - ISSN 2575-1077. - 4:8(2021), p. e202101019. [10.26508/LSA.202101019]

Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene

Lombardo A.;Doglioni C.;Tonon G.
2021-01-01

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.
2021
Cell Cycle Proteins
Cell Line
Cell Proliferation
Gene Expression Regulation, Neoplastic
Genomic Instability
HEK293 Cells
HeLa Cells
Humans
Mitosis
Pseudogenes
Chromosome Fragile Sites
Gene Deletion
Up-Regulation
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/126805
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