| RRC ID |
85233
|
| Author |
Okamoto K, Mihara Y, Ogasawara S, Murakami T, Ohmori S, Mori T, Umata T, Kawasaki Y, Hirano K, Yano H, Tsuneoka M.
|
| Title |
Interaction Between PHF8 and a Segment of KDM2A, Which Is Controlled by the Phosphorylation Status at a Specific Serine in an Intrinsically Disordered Region of KDM2A, Regulates rRNA Transcription and Cell Proliferation in a Breast Cancer Cell Line.
|
| Journal |
Biomolecules
|
| Abstract |
Mild starvation due to low concentrations of an inhibitor of glycolysis, 2-deoxy-D-glucose, activates AMP-activated protein kinase (AMPK) and lysine-specific demethylase 2A (KDM2A) to reduce rRNA transcription and cell proliferation in breast cancer cells. However, the mechanisms of how AMPK regulates KDM2A are unknown. Here, we found that PHD finger protein 8 (PHF8) interacted with KDM2A and contributed to the reduction in rRNA transcription and cell proliferation by 2-deoxy-D-glucose in a breast cancer cell line, MCF-7. We analyzed how KDM2A bound PHF8 in detail and found that PHF8 interacted with KDM2A via two regions of KDM2A. One of the regions contained an intrinsically disordered region (IDR). IDRs can show rapidly switchable protein-protein interactions. Deletion of the PHF8-binding region activated KDM2A to reduce rRNA transcription, and 2-deoxy-D-glucose reduced the interaction between PHF8 and the KDM2A fragment containing the PHF8-binding region. A 2-deoxy-D-glucose or AMPK activator dephosphorylated KDM2A at Ser731, which is located on the N-terminal side of the PHF8-binding region. Replacement of Ser731 by Ala decreased binding of PHF8 to the KDM2A fragment that contains the PHF8-binding region and Ser731 and reduced rRNA transcription and cell proliferation. These results suggest that the mode of interaction between KDM2A and PHF8 is regulated via dephosphorylation of KDM2A through AMPK to control rRNA transcription, and control of the phosphorylation state of Ser731 would be a novel target for breast cancer therapy.
|
| Volume |
15(5)
|
| Published |
2025-5-2
|
| DOI |
10.3390/biom15050661
|
| PII |
biom15050661
|
| PMID |
40427554
|
| PMC |
PMC12109296
|
| MeSH |
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Cell Proliferation
F-Box Proteins* / chemistry
F-Box Proteins* / genetics
F-Box Proteins* / metabolism
Female
Histone Demethylases
Humans
Jumonji Domain-Containing Histone Demethylases* / chemistry
Jumonji Domain-Containing Histone Demethylases* / genetics
Jumonji Domain-Containing Histone Demethylases* / metabolism
MCF-7 Cells
Phosphorylation
Protein Binding
RNA, Ribosomal* / genetics
RNA, Ribosomal* / metabolism
Serine / metabolism
Transcription Factors* / chemistry
Transcription Factors* / genetics
Transcription Factors* / metabolism
Transcription, Genetic
|
| IF |
4.082
|
| Resource |
| Human and Animal Cells |
293T(RCB2202) |
