Regulation of the SIAH2-HIF-1 Axis by Protein Kinases and Its Implication in Cancer Therapy.

Dazhong Xu,Cen Li

doi:10.3389/fcell.2021.646687

Abstract

The cellular response to hypoxia is a key biological process that facilitates adaptation of cells to oxygen deprivation (hypoxia). This process is critical for cancer cells to adapt to the hypoxic tumor microenvironment resulting from rapid tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor and a master regulator of the cellular response to hypoxia. The activity of HIF-1 is dictated primarily by its alpha subunit (HIF-1α), whose level and/or activity are largely regulated by an oxygen-dependent and ubiquitin/proteasome-mediated process. Prolyl hydroxylases (PHDs) and the E3 ubiquitin ligase Von Hippel-Lindau factor (VHL) catalyze hydroxylation and subsequent ubiquitin-dependent degradation of HIF-1α by the proteasome. Seven in Absentia Homolog 2 (SIAH2), a RING finger-containing E3 ubiquitin ligase, stabilizes HIF-1α by targeting PHDs for ubiquitin-mediated degradation by the proteasome. This SIAH2-HIF-1 signaling axis is important for maintaining the level of HIF-1α under both normoxic and hypoxic conditions. A number of protein kinases have been shown to phosphorylate SIAH2, thereby regulating its stability, activity, or substrate binding. In this review, we will discuss the regulation of the SIAH2-HIF-1 axis via phosphorylation of SIAH2 by these kinases and the potential implication of this regulation in cancer biology and cancer therapy.

Highlights

Cellular response to low oxygen tension is one of the most fundamental biological processes that determine the survival of cells under the hypoxic condition (Bruick, 2003; Kaelin and Ratcliffe, 2008)
The list of protein kinases that regulate Seven in Absentia Homolog 2 (SIAH2) will likely become longer over time
The regulation of the Hypoxiainducible factor 1 (HIF-1) pathway and the cellular hypoxic response by SIAH2 highlights the potential importance of this protein in converging inputs from multiple kinases to the hypoxia-inducible factors (HIFs)-1 pathway

Summary

Introduction

Cellular response to low oxygen tension (hypoxia) is one of the most fundamental biological processes that determine the survival of cells under the hypoxic condition (Bruick, 2003; Kaelin and Ratcliffe, 2008). The regulation of the HIF-1 pathway and hypoxic response by mediating proteasomal degradation of PHDs is one of the most prominent and well-established functions of SIAH2 (Nakayama and Ronai, 2004; Nakayama et al, 2004, 2009; Qi et al, 2013). Other functions of DYRK2 include acting as a scaffold for the EDVP E3 ubiquitin ligase complex to control cell cycle progression through the G2/M phase and regulating the Hedgehog signaling pathway by promoting the proteasomal degradation of the transcription factor GLI2 through direct phosphorylation (Maddika and Chen, 2009; Singh and Lauth, 2017).

Results

Conclusion