摘要
Since the recent discovery of cancer cell-intrinsic programmed cell death protein-1(PD-1),the mechanisms that manipulate PD-1 functions in tumor development beyond its immune checkpoint roles have become attractive research topics in oncology.Our previous study validated that PD-1 exists in lung cancer cells and is directly transactivated by p53 in a DNA-binding domain(DBD)acetylation-dependent manner.Here,we report that the carboxyl-terminal domain(CTD)of p53 likewise participates in PD-1 transcriptional regulation in cancer cells under different regulatory mechanisms.By mutating the lysine residues within the CTD to mimic either acetylationdeficient or fully acetylated status,we proved that acetylated CTD dramatically impeded p53-mediated transactivation of PD-1.Furthermore,we identified bromodomain-containing protein 4(BRD4)as a transcriptional coactivator of p53 that facilitates p53-mediated PD-1 transcription.Mechanistically,BRD4 specifically bound to the unacetylated CTD of p53,while CTD acetylation almost completely destroyed the BRD4-p53 interaction and thus led to compromised PD-1 expression.Collectively,this study unveils an alternative mechanism of p53 acetylation-directed PD-1 transcriptional regulation,which would broaden our current understanding of the molecular regulatory network of cancer cell-intrinsic PD-1.
基金
This research was supported by the National Natural Science Foundation of China(81872311,82073132 and 82122054)
Beijing Municipal Natural Science Foundation(7192126)
AMS Innovation Fund for Medical Sciences(2021-I2M-1-016).
