Open AccessAn unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation
Author(s) -
Zhijie Cao,
Ning Kon,
Yajing Liu,
Wenbin Xu,
Jia Wen,
Han Yao,
Mi Zhang,
Zhen Wu,
Yan Xin,
Weiguo Zhu,
Wei Gu,
Donglai Wang
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abf4148
Subject(s) - acetylation , cancer cell , cancer research , transcription factor , histone , regulator , hdac1 , chromatin , biology , acetyltransferase , suppressor , histone acetyltransferase , histone deacetylase , cancer , carcinogenesis , chemistry , microbiology and biotechnology , biochemistry , genetics , gene
Cancer cell-intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 promoter, selectively facilitating PD-1 transcription by enhancing local chromatin acetylation. Reexpression of PD-1 in cancer cells inhibited tumor growth, whereas depletion of cancer cell-intrinsic PD-1 compromised p53-dependent tumor suppression. Moreover, histone deacetylase inhibitor (HDACi) activated PD-1 in an acetylated p53-dependent manner, supporting a synergistic effect by HDACi and p53 on tumor suppression via stimulating cancer cell-intrinsic PD-1. Our study reveals a mechanism for activating cancer cell-intrinsic PD-1 and indicates that p53-mediated PD-1 activation is critically involved in tumor suppression in an immunity-independent manner.