The DOI matches its Crossref record; 64 of the 65 references it cites were found in a registry or an index.
Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis.
Open accessAbstract
The histone demethylase PHF8 has been implicated in multiple pathological disorders, including X-linked mental retardation and tumorigenesis. However, it is not clear how the abundance and function of PHF8 are regulated. Here, we report that PHF8 physically associates with the deubiquitinase USP7. Specifically, we demonstrated that USP7 promotes deubiquitination and stabilization of PHF8, leading to the upregulation of a group of genes, including cyclin A2, that are critical for cell growth and proliferation. The USP7-encoding gene was also transcriptionally regulated by PHF8, via positive feedback. USP7 was overexpressed in breast carcinomas, and the level of expression positively correlated with expression of PHF8 and cyclin A2 and with the histological grade of breast cancer. We showed that USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2 and that the interaction between USP7 and PHF8 is augmented during DNA damage. Moreover, USP7-promoted PHF8 stabilization conferred cellular resistance to genotoxic insults and was required for the recruitment of BLM and KU70, which are both essential for DNA double-strand break repair. Our study mechanistically links USP7 to epigenetic regulation and DNA repair. Moreover, these data support the pursuit of USP7 and PHF8 as potential targets for breast cancer intervention, especially in combination with chemo- or radiotherapies.
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“several well-characterized USP7 substrates, including p53 30, PHF8 31, and PLK1 32, are known to be key regulators of cell cycle progression and cellular proliferation—processes fundamental to HSC maintenance.”
From USP7 sustains hematopoietic stem cell homeostasis partially via PU.1 stabilization (2026) · cites this paper as [31]
In the citing paper
“In addition to the transcriptional regulation of cyclin A2, PHF8 interacts with Ku70 and the BLM helicase to facilitate their localization to sites of DSBs.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“The depletion of USP7 from cells has been found to greatly compromise the repair of DSBs by either NHEJ or HR (Wang et al., 2016; An et al., 2017).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“Indeed, the recruitment of either protein is impaired in cells following PHF8 or USP7 depletion (Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“Indeed, USP7, PHF8 and cyclin A2 were all found to be upregulated in several breast cancers, as well as in colon and rectum cancers, compared to adjacent tissues (Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“A strong correlation has also been observed between USP7 and the cell cycle regulatory protein PHF8 (Wang et al., 2016). This correlation was observed in clinical breast cancer samples and increased with histological grade.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“As we discussed in the Cell Cycle Regulation section, USP7 deubiquitinates and stabilizes PHF8, allowing the latter to upregulate gene targets involved in cell cycle progression, including cyclin A2 (Liu et al., 2010; Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“USP7 has also been suggested as a potential target for sensitization in breast cancer treatment, where USP7 is frequently upregulated and confers resistance to genotoxic insult, by stabilizing PHF8 (Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
In the citing paper
“USP7 has also been suggested as a potential target for sensitization in breast cancer treatment, where USP7 is frequently upregulated and confers resistance to genotoxic insult, by stabilizing PHF8 (Wang et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Wang et al., 2016
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Citations
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53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
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Zhang, H., Deng, T., Ge, S., Liu, Y., Bai, M., Zhu, K., Fan, Q., Li, J., Ning, T., Tian, F., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0619-z · Cited by 303
RetractedChen, S., Zhu, S., Pei, X., Qiu, B., Xiong, D., Long, X., Lin, K., Lü, F., Xu, J., & Wu, Y. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01448-x · Cited by 263
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Gavory, G., O'Dowd, C. R., Helm, M. D., Flasz, J., Arkoudis, E., Dossang, A., Hughes, C., Cassidy, E., McClelland, K., Odrzywol, E., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2528 · Cited by 224
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Metadata
- Authors
- Wang, Q., Ma, S., Song, N., Li, X., Liu, L., Yang, S., Ding, X., Shan, L., Zhou, X., Su, D., Wang, Y., Zhang, Q., Liu, X., Yu, N., Zhang, K., Shang, Y., Yao, Z., & Shi, L.
- Affiliations
- Tianjin Medical University (CN)
- Chinese Academy of Sciences (CN)
- Peking University (CN)
- Corresponding author
- Yao, Zhi
- Shi, Lei
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-05-16
- Volume
- 126
- Issue
- 6
- Pages
- 2205-2220
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4887182
- OpenAlex
- W2381681988
- Cited by
- 206
- References
- 65
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 25 · 2023: 19 · 2022: 23 · 2021: 17 · 2020: 30 · 2019: 24 · 2018: 16 · 2017: 18 · 2016: 5
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tianjin Medical University
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- PHF8, USP7, histone demethylase, protein stabilization, deubiquitination, breast cancer, cyclin A2, DNA double-strand break repair, BLM, Ku70, DNA damage response, epigenetic regulation, positive feedback loop, histone demethylation
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Breast Neoplasms, DNA Damage, DNA Repair, Enzyme Stability, Female, Humans, Transcription Factors, Up-Regulation, RNA, Small Interfering, Ubiquitin Thiolesterase, Epigenesis, Genetic, Protein Interaction Domains and Motifs, Histone Demethylases, Cyclin A2, MCF-7 Cells, Carcinogenesis
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