Journal
SCIENCE ADVANCES
Volume 7, Issue 14, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf4148
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Funding
- National Natural Science Foundation of China [81872311, 82073132]
- Beijing Municipal Natural Science Foundation [7192126]
- National Key R&D Program of China [2019YFC1005200, 2019YFC1005201]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-1-008, 2018-I2M-1-002]
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The study revealed that PD-1 in cancer cells is a direct target of the tumor suppressor p53, with its transcription being influenced by acetylation of p53. Acetylated p53 enhances PD-1 transcription, facilitating activation of cancer cell-intrinsic PD-1 and inhibiting tumor growth.
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.
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