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Review
. 2021 Feb 18:9:648808.
doi: 10.3389/fcell.2021.648808. eCollection 2021.

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer

Cen Zhang  1 , Juan Liu  1 , Jianming Wang  1 , Tianliang Zhang  1 , Dandan Xu  1 , Wenwei Hu  1 , Zhaohui Feng  1
Affiliations
Review

The Interplay Between Tumor Suppressor p53 and Hypoxia Signaling Pathways in Cancer

Cen Zhang et al. Front Cell Dev Biol. .

Abstract

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.

Keywords: HIF; cancer; cancer therapy; hypoxia; mutant p53; p53; tumor suppressor.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The regulation of the p53 signaling by hypoxia. Hypoxia regulates p53 in a context-dependent manner. Hypoxia positively regulates the mRNA levels, translation, protein levels, and activities of p53 through different mechanisms. At the same time, hypoxia can negatively regulate p53 mRNA levels, protein levels, and activities in certain types of cells under certain conditions.
FIGURE 2
FIGURE 2
The regulation of the hypoxia and HIF signaling by p53. p53 represses the protein levels and activities of HIF-1α and HIF-1β through various mechanisms.
FIGURE 3
FIGURE 3
The biological outcomes of the interplay between the p53 and hypoxia signaling pathways. p53 cross-talks with hypoxia to regulate cell cycle arrest, apoptosis, autophagy, cell proliferation, angiogenesis, metastasis, metabolic reprogramming, and cell stemness in cancer.
See this image and copyright information in PMC

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