Although nuclear type 2C protein phosphatase (PP2Cä) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2Cä levels with cancer development remain elusive. Here, we found that aberrant PP2Cä 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. PP2Cä, via dephosphorylation of ATM, suppresses DNA damage-induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2Cä levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2Cä inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft-bearing nude mice. Together, our data indicate that PP2Cä impairs p53 acetylation and DNA damage response by compromising BRCA1 function.
Acetylation Animals