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
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cells and Cell Culture
2.2. Introduction of Plasmids and siRNAs into Mammalian Cells
2.3. Plasmids
2.4. Western Blotting of Cell Lysates and Immunoprecipitation
2.5. Methods for Tissue Processing and Immunostaining
2.6. Metabolic Labeling Assay of Newly Synthesized RNA Using 5-Ethynyl Uridine (EU)
2.7. Detection of Phosphorylated Peptide by Phos-Tag
2.8. Production of Anti-Phosphorylated Ser 731
2.9. RNA Extraction and Quantitative Reverse Transcription–Polymerase Chain Reaction (qRT-PCR)
2.10. Statistical Analyses
3. Results
3.1. PHF8 Binds to KDM2A and Is Required for Reduction in rRNA Transcription by Mild Starvation
3.2. Identification of KDM2A Regions That Are Involved in Binding to PHF8
3.3. KDM2A with Deleted a Region Reduces rRNA Transcription More Strongly than Wild-Type KDM2A
3.4. KDM2A Fragment That Contains the a Region Shows Switchable Interaction with PHF8
3.5. A Dephosphorylation-Mimicked Mutation at Ser731 Reduced the Interaction Between PHF8 and the KDM2A Fragments and rRNA Transcription
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AMPK | AMP-activated protein kinase |
2DG | 2-deoxy-D-glucose |
IDR | intrinsically disordered region |
KDM2A | lysine-specific demethylase 2A |
PHF8 | PHD Finger Protein 8 |
PHD | plant homeodomain |
KD | knockdown |
HP1 | heterochromatin protein 1 |
HEK | human embryonic kidney |
siRNA | small interfering RNA |
GFP | green fluorescent protein |
HRP | horseradish peroxidase |
EU | 5-ethynyl uridine |
ECL | electrogenerated chemiluminescence |
qRT-PCR | quantitative reverse transcription–polymerase chain reaction |
LRR | leucine-rich repeats |
AICAR | 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside |
B2M | β2-microglobulin |
Pol I | RNA polymerase I |
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Stealth siRNA | siRNA Sequence |
---|---|
siKDM2A | 5′-GAACCCGAAGAAGAAAGGAUUCGUU-3′ |
siPHF8#1 | 5′-CAACAAAUGCCAAUCUGACUCUCUU-3′ |
siPHF8#2 | 5′-GAGCUCCGGAGUAGGACUUUUGACA-3′ |
control siRNA | Stealth RNAi Negative Control Medium GC Duplex, Thermo Fisher |
Antigen | Antibody |
---|---|
KDM2A | Rabbit anti-KDM2A polyclonal antibody (Proteintech, 24311-1-AP) Rabbit anti-KDM2A monoclonal antibody (Abcam, ab191387) Anti-FbxL11 (KDM2A) antibody (Abcam, ab99242) |
PHF8 | Rabbit anti-PHF8 monoclonal antibody (Cell Signaling Technology, PHF8 (E6K3Y)) |
Flag | Rabbit polyclonal anti-Flag antibody (Sigma, F7425) Mouse monoclonal anti-Flag antibody (M2, Sigma, F1804) |
GFP | Rabbit polyclonal anti-GFP antibody (Abcam, ab290) Mouse monoclonal anti-GFP antibody (Santa Cruz, ab290) |
β-actin | Mouse monoclonal anti-β-actin antibody (Sigma, AC-15) |
Rabbit IgG | Goat-rabbit IgG-horseradish peroxidase (HRP) (Abcam, ab6721) Goat anti-rabbit IgG-HRP (Santa Cruz, sc-2054, human and mouse IgG adsorbed) Goat anti-rabbit IgG(H&L)-Cy3 conjugated (Zymed, #81-6115) |
Mouse IgG | Goat anti-mouse IgG-HRP (Santa Cruz, sc-2005) |
Gene | Primer Sequence |
---|---|
pre-rRNA | Forward: 5′-GCTGACACGCTGTCCTCTG-3′ Reverse: 5′-TCGGACGCGCGAGAGAAC-3′ |
KDM2A | Forward: 5′-TCCCCACACACATTTTGACATC-3′ Reverse: 5′-GGGGTGGCTTGAGAGATCCT-3′ |
PHF8 | Forward: 5′-AGCCCTACGTTCGTCAGAGA-3′ Reverse: 5′-CAACCCATCCTTCTTCAGGA-3′ |
Polr2a | Forward: 5′-ATCTCTCCTGCCATGACACC-3′ Reverse: 5′-AGACCAGGCAGGGGAGTAAC-3′ |
β-actin | Forward: 5′-CGTCTTCCCCTCCATCGT-3′ Reverse: 5′-GAAGGTGTGGTGCCAGATTT-3 |
B2M | Forward: 5′-CTCGCGCTACTCTCTCTTTCT-3′ Reverse: 5′-TGTCGGATTGATGAAACCCAG-3′ |
PHF8 score | Papillotubular | Solid tubular | Scirrhpous | Mucinous | Miceopapillary | |||||||||||||||||||||
4 | 5 | 6 | 7 | 8 | 4 | 5 | 6 | 7 | 8 | 4 | 5 | 6 | 7 | 8 | 4 | 5 | 6 | 7 | 8 | 4 | 5 | 6 | 7 | 8 | ||
Number | 2 | 2 | 2 | 8 | 3 | 0 | 1 | 1 | 0 | 0 | 1 | 1 | 4 | 5 | 3 | 0 | 0 | 2 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | |
HER2 | 0 | 0 | 0 | 0 | 6 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 4 | 2 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
1 | 1 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |
2 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | |
3 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | |
ER | − | 0 | 1 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
+ | 2 | 1 | 1 | 6 | 3 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 4 | 4 | 3 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
PgR | − | 0 | 2 | 2 | 2 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
+ | 2 | 0 | 0 | 6 | 3 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 3 | 4 | 3 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | |
Triple Negative | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Species | Total AA | JmjC Domain | A Region | IDR-4 | IDR-4 (AA 700-808) |
---|---|---|---|---|---|
Mouse | AA 1161 (97.3%) | 168/169 (99.4%) | 118/125 (94.4%) | 208/217 (95.8%) | 108/109 (99%) |
Chicken | AA 1168 (86%) | 156/169 (92%) | 95/125 (76%) | 171/217 (78.8%) | 100/108 (91.7%) |
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Okamoto, K.; Mihara, Y.; Ogasawara, S.; Murakami, T.; Ohmori, S.; Mori, T.; Umata, T.; Kawasaki, Y.; Hirano, K.; Yano, H.; et al. 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. Biomolecules 2025, 15, 661. https://doi.org/10.3390/biom15050661
Okamoto K, Mihara Y, Ogasawara S, Murakami T, Ohmori S, Mori T, Umata T, Kawasaki Y, Hirano K, Yano H, et al. 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. Biomolecules. 2025; 15(5):661. https://doi.org/10.3390/biom15050661
Chicago/Turabian StyleOkamoto, Kengo, Yutaro Mihara, Sachiko Ogasawara, Takashi Murakami, Sinya Ohmori, Tetsuya Mori, Toshiyuki Umata, Yuki Kawasaki, Kazuya Hirano, Hirohisa Yano, and et al. 2025. "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" Biomolecules 15, no. 5: 661. https://doi.org/10.3390/biom15050661
APA StyleOkamoto, K., Mihara, Y., Ogasawara, S., Murakami, T., Ohmori, S., Mori, T., Umata, T., Kawasaki, Y., Hirano, K., Yano, H., & Tsuneoka, M. (2025). 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. Biomolecules, 15(5), 661. https://doi.org/10.3390/biom15050661