A truncated and catalytically inactive isoform of KDM5B histone demethylase accumulates in breast cancer cells and regulates H3K4 tri-methylation and gene expression.
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
25
07
2022
accepted:
21
12
2022
revised:
20
12
2022
medline:
22
6
2023
pubmed:
26
1
2023
entrez:
25
1
2023
Statut:
ppublish
Résumé
KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the specific context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows a much faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and -gamma response. We discuss the relevance of this finding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.
Identifiants
pubmed: 36697763
doi: 10.1038/s41417-022-00584-w
pii: 10.1038/s41417-022-00584-w
pmc: PMC10281864
doi:
Substances chimiques
Histones
0
Histone Demethylases
EC 1.14.11.-
Protein Isoforms
0
KDM5B protein, human
EC 1.14.11.-
Nuclear Proteins
0
Repressor Proteins
0
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
822-832Informations de copyright
© 2023. The Author(s).
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