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PP2Cδ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer
- Source :
- Science Advances
- Publication Year :
- 2019
- Publisher :
- American Association for the Advancement of Science (AAAS), 2019.
-
Abstract
- Aberrant PP2Cδ inhibits p300-mediated p53 acetylation and activation via the ATM/BRCA1 pathway, leading to cancer progression.<br />Although nuclear type 2C protein phosphatase (PP2Cδ) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2Cδ levels with cancer development remain elusive. Here, we found that aberrant PP2Cδ activity decreases p53 acetylation and its transcriptional activity and suppresses doxorubicin-induced cell apoptosis. Mechanistically, we show that BRCA1 facilitates p300-mediated p53 acetylation by complexing with these two proteins and that S1423/1524 phosphorylation is indispensable for this regulatory process. PP2Cδ, via dephosphorylation of ATM, suppresses DNA damage–induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2Cδ levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2Cδ inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft–bearing nude mice. Together, our data indicate that PP2Cδ impairs p53 acetylation and DNA damage response by compromising BRCA1 function.
- Subjects :
- endocrine system diseases
DNA damage
Phosphatase
Mice, Nude
Apoptosis
Breast Neoplasms
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
medicine.disease_cause
Dephosphorylation
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cell Line, Tumor
medicine
Animals
Humans
Phosphorylation
skin and connective tissue diseases
Research Articles
Cancer
030304 developmental biology
0303 health sciences
Multidisciplinary
BRCA1 Protein
Chemistry
SciAdv r-articles
Life Sciences
Acetylation
3. Good health
Cell biology
Protein Phosphatase 2C
030220 oncology & carcinogenesis
MCF-7 Cells
Female
Tumor Suppressor Protein p53
Carcinogenesis
E1A-Associated p300 Protein
DNA
Research Article
DNA Damage
Signal Transduction
Subjects
Details
- ISSN :
- 23752548
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Science Advances
- Accession number :
- edsair.doi.dedup.....dbc5c36066f1f20b624cf67d4f3d09b8