Aberrant JmjC domain-containing protein 8 (JMJD8) expression promotes activation of AKT and tumor epithelial-mesenchymal transition.
Cell Line, Tumor
Cell Movement
Cell Nucleus
/ metabolism
DNA Methylation
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Glycogen Synthase Kinase 3 beta
/ metabolism
Histone-Lysine N-Methyltransferase
/ metabolism
Humans
Jumonji Domain-Containing Histone Demethylases
/ genetics
Mutation
Neoplasm Invasiveness
/ pathology
Neoplasms
/ genetics
Phosphorylation
Protein Binding
/ genetics
Proto-Oncogene Proteins c-akt
/ metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
/ metabolism
Signal Transduction
/ genetics
beta Catenin
/ metabolism
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
07
05
2020
accepted:
21
08
2020
revised:
06
08
2020
pubmed:
4
9
2020
medline:
15
12
2020
entrez:
4
9
2020
Statut:
ppublish
Résumé
Posttranslational modifications of histone and nonhistone proteins greatly influence numerous molecular events in multiple diseases. Jumonji domain-containing proteins are a family functioning as histone demethylase. Jumonji domain-containing protein 8 (JMJD8) is Jumonji C (JmjC) domain-only member of this family, and its physiological functions remain largely unknown. In this study, we investigated the mechanism by which aberrant JMJD8 stimulates phosphorylation of AKT and activate AKT/GSK3β/β-catenin signaling pathway thereby promotes tumor cell epithelial-mesenchymal transition (EMT). We demonstrated that knockdown of JMJD8 increased the interaction of SETDB1 and phosphoinositide-dependent kinase 1 (PDK1) with AKT1 and resulted in enhanced trimethylation of AKT1 at lysine 142 (K142), which is crucial for cell membrane recruitment, phosphorylation, and activation of AKT. Moreover, the mutation of histidine 200 of JMJD8 (JMJD8-H200Q) disrupted its binding with AKT1 and increased interaction of SETDB1 and PDK1 with AKT1. Furthermore, histone demethylase jumonji domain-containing protein 2B functioned as an adapter to recruit β-catenin to the methylated AKT1 upon JMJD8 depression, which facilitated the phosphorylation of β-catenin at Ser552 and its accumulation in cell nucleus where the activated β-catenin transcriptionally stimulated the expression of genes involved in EMT. In conclusion, our data unraveled a novel role of JMJD8 in regulating the migration and invasion of tumor via modulating AKT methylation and activation. In addition, this study showed that JMJD8 is a potential biomarker and drug design target for tumor EMT.
Identifiants
pubmed: 32879443
doi: 10.1038/s41388-020-01446-1
pii: 10.1038/s41388-020-01446-1
doi:
Substances chimiques
CTNNB1 protein, human
0
PDK1 protein, human
0
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
0
beta Catenin
0
JMJD8 protein, human
EC 1.14.11.-
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
KDM4B protein, human
EC 1.14.11.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
SETDB1 protein, human
EC 2.1.1.43
AKT1 protein, human
EC 2.7.11.1
GSK3B protein, human
EC 2.7.11.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6451-6467Commentaires et corrections
Type : ErratumIn
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