Aberrant JmjC domain-containing protein 8 (JMJD8) expression promotes activation of AKT and tumor epithelial-mesenchymal transition.

Abstract

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.

• Authors: Yao Su, Xueying Wang, Zhen Guo, Jun Wang
• Journal: Oncogene (Oncogene) Vol. 39 Issue 41 Pg. 6451-6467 (10 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32879443 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CTNNB1 protein, human
• PDK1 protein, human
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• beta Catenin
• JMJD8 protein, human
• Jumonji Domain-Containing Histone Demethylases
• KDM4B protein, human
• Histone-Lysine N-Methyltransferase
• SETDB1 protein, human
• AKT1 protein, human
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt

Topics

• 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, metabolism)
• Mutation
• Neoplasm Invasiveness (pathology)
• Neoplasms (genetics, pathology)
• Phosphorylation
• Protein Binding (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase (metabolism)
• Signal Transduction (genetics)
• beta Catenin (metabolism)