ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells.

Détails

Ressource 1Télécharger: s41419-020-03231-0.pdf (1840.42 [Ko])
Etat: Public
Version: de l'auteur
Licence: CC BY 4.0
ID Serval
serval:BIB_8A98DCCB86FF
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells.
Périodique
Cell death & disease
Auteur(s)
Constantin D., Widmann C.
ISSN
2041-4889 (Electronic)
Statut éditorial
Publié
Date de publication
30/11/2020
Peer-reviewed
Oui
Volume
11
Numéro
11
Pages
1019
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
It is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that nonresponders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Here, we initially focused on the bleomycin genotoxin because of the limited information about the genes implicated in the sensitivity or resistance to this compound. Using a whole-genome CRISPR/Cas9 gene knockout approach, we identified ASH2L, a core component of the H3K4 methyl transferase complex, as a protein required for bleomycin sensitivity in L1236 Hodgkin lymphoma. Knocking down ASH2L in these cells and in the NT2D1 testicular cancer cell line rendered them resistant to bleomycin, etoposide, and cisplatin but did not affect their sensitivity toward ATM or ATR inhibitors. ASH2L knockdown decreased cell proliferation and facilitated DNA repair via homologous recombination and nonhomologous end-joining mechanisms. Data from the Tumor Cancer Genome Atlas indicate that patients with testicular cancer carrying alterations in the ASH2L gene are more likely to relapse than patients with unaltered ASH2L genes. The cell models we have used are derived from cancers currently treated either partially (Hodgkin's lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. In situations where tumors are expressing low levels of ASH2L, which may allow them to resist genotoxic treatment, the use of ATR or ATM inhibitors may be more efficacious as our data indicate that ASH2L knockdown does not affect sensitivity to these inhibitors.
Mots-clé
Ash2L, Hodgkin lymphoma, testicular cancer, personalized medicine, DNA repair
Pubmed
Open Access
Oui
Création de la notice
07/12/2020 14:21
Dernière modification de la notice
16/07/2021 6:11
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