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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
An unexpected role for p53 in regulating cancer cell-intrinsic PD-1 by acetylation
Zhijie Cao1, Ning Kon2, Yajing Liu1
1State Key Laboratory of Medical Molecular Biology and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
Abstract:
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.
Insights
The tumor suppressor p53 directly regulates programmed cell death protein-1 (PD-1) in cancer cells. This p53-PD-1 pathway inhibits tumor growth independently of the immune system.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cancer cell-intrinsic programmed cell death protein-1 (PD-1) acts as a tumor regulator, but its control mechanisms within cancer cells remain unclear.
- The precise role of PD-1 in tumor behavior modulation is complex and not fully understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms of cancer cell-intrinsic PD-1.
- To identify the relationship between tumor suppressor p53 and PD-1 expression in cancer cells.
Main Methods:
- Investigated PD-1 as a direct target of p53.
- Analyzed the role of p53 acetylation (K120/164) in PD-1 transcription.
- Examined the effect of PD-1 reexpression and depletion on tumor growth.
- Assessed the impact of histone deacetylase inhibitors (HDACi) on PD-1 activation.
Main Results:
- PD-1 was identified as a direct transcriptional target of p53.
- p53 acetylation at K120/164 is crucial for p53-mediated PD-1 transcription.
- Reexpression of PD-1 inhibited tumor growth; PD-1 depletion impaired p53-dependent tumor suppression.
- HDAC inhibitors activated PD-1 in an acetylated p53-dependent manner, showing synergy with p53.
Conclusions:
- A novel mechanism for activating cancer cell-intrinsic PD-1 via p53 acetylation was revealed.
- p53-mediated PD-1 activation contributes to tumor suppression independently of the immune system.
- HDAC inhibitors enhance tumor suppression by stimulating cancer cell-intrinsic PD-1 through acetylated p53.
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