PP2C∂ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer

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