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

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

doi:10.3389/fcell.2021.648808

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.

Highlights

Extensive studies have established that p53 is a key tumor suppressor, and disruption of the p53 function is a prerequisite for the initiation and/or progression of many human cancers
Some studies reported that MDM2 can increase the levels of hypoxia-inducible factor (HIF)-1α (Nieminen et al, 2005; LaRusch et al, 2007), which suggests that the effect of MDM2 on HIF1α may vary depending on the cell/tissue type and severity of hypoxia
These studies provide evidence of targeting the hypoxia/HIF and p53 signaling pathways in cancer simultaneously for improved cancer treatment, which will inspire many future studies and better strategies in cancer therapies. Both hypoxia and p53 signaling pathways in cancer have been extensively studied for decades

Summary

INTRODUCTION

Extensive studies have established that p53 is a key tumor suppressor, and disruption of the p53 function is a prerequisite for the initiation and/or progression of many human cancers. MDM4 negatively regulates p53 in both MDM2dependent and -independent manners; MDM4 interacts with MDM2 and promotes MDM2−mediated ubiquitination and degradation of p53, and interacts with p53 to suppress the transcriptional activities of p53 (Zhao et al, 2014; KarniSchmidt et al, 2016; Haupt et al, 2019) Both MDM2 and MDM4 are overexpressed in a variety of tumors, which result in the downregulation of p53 protein levels and activities, leading to tumor initiation and/or progression (Karni-Schmidt et al, 2016; Donehower et al, 2019; Haupt et al, 2019). Different positive and negative feedback loops are formed between p53 and p53 regulators to tightly regulate p53 levels and activities (Hock and Vousden, 2014; Levine, 2019; Liu Y. et al, 2019)

HYPOXIA AND HIF SIGNALING PATHWAY

Cell Survival and Proliferation

Metabolic Reprogramming

Cell Stemness

Findings

DISCUSSION