PP2Cδ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer

Although nuclear type 2C protein phosphatase (PP2C delta) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2C delta levels with cancer development remain elusive. Here, we found that aberrant PP2C delta 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. PP2C delta, via dephosphorylation of ATM, suppresses DNA damage-induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2C delta levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2C delta inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft-bearing nude mice. Together, our data indicate that PP2C delta impairs p53 acetylation and DNA damage response by compromising BRCA1 function.