The Role of Sumoylation in the Response to Hypoxia: An Overview

Abstract

Sumoylation is the covalent attachment of the small ubiquitin-related modifier (SUMO) to a vast variety of proteins in order to modulate their function. Sumoylation has emerged as an important modification with a regulatory role in the cellular response to different types of stress including osmotic, hypoxic and oxidative stress. Hypoxia can occur under physiological or pathological conditions, such as ischemia and cancer, as a result of an oxygen imbalance caused by low supply and/or increased consumption. The hypoxia inducible factors (HIFs), and the proteins that regulate their fate, are critical molecular mediators of the response to hypoxia and modulate procedures such as glucose and lipid metabolism, angiogenesis, erythropoiesis and, in the case of cancer, tumor progression and metastasis. Here, we provide an overview of the sumoylation-dependent mechanisms that are activated under hypoxia and the way they influence key players of the hypoxic response pathway. As hypoxia is a hallmark of many diseases, understanding the interrelated connections between the SUMO and the hypoxic signaling pathways can open the way for future molecular therapeutic interventions.

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

“…Thus, there is the oxygen-sensitive mechanism regulating the stability, subcellular localization and functional activity of HIF-1α. Besides, certain protein kinases and phosphatases, histone lysine methylases and demethylases, acetyl transferases and deacetylases, chaperones and a small ubiquitin-related modifier (SUMO) E3 ligase can directly or indirectly affect the HIF-1α stability and its capacity to form the active HIF-1 heterodimer in the nucleus [ 19 , 20 , 21 , 22 , 23 , 24 ]. At the expression level, HIF-1α can also be regulated by a signal transducer and activator of transcription 3 (STAT3) [ 25 ], nuclear factor-κB (NF-κB) [ 26 ], microRNAs [ 15 , 27 , 28 ] or long noncoding RNAs [ 15 , 29 , 30 , 31 , 32 ], c-Myc [ 33 ], angiotensin II [ 34 ] and signal transduction pathways involving stress- or mitogen-activated kinases [ 35 , 36 ], phosphoinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR) [ 37 , 38 , 39 ].…”

Lessons from Comparison of Hypoxia Signaling in Plants and Mammals

“…However, the regulation of HIF1α under hypoxia is more complex as it is, in fact, the target of many post-translational modifications [ 21 ]. Among these other post-translational modifications, the sumoylation of HIF1α contributes to its ubiquitin-dependent stability, but the mechanisms underlying the role of SUMO remain somewhat unclear, as opposite models have been proposed ( Figure 1 ).…”

“…In both plants and mammals, protein degradation mediated by the ubiquitin/proteasome system is central to this regulation. In recent years, the ubiquitin-like protein SUMO (Small Ubiquitin-like Modifier) has also been shown to play an important role in the regulation of hypoxia response and sensing mechanisms in plants and mammals [ 21 , 22 , 23 , 24 ]. For example, the complement of sumoylated proteins changes upon hypoxia in mammalian cells, with an overall increase in sumoylated proteins [ 25 ].…”

Redox tolerance and metabolic reprogramming in solid tumors

“…Hypoxia is a response to an imbalance in the oxygen content due to either increased consumption or low supply. Hypoxia-inducible factors (HIFs) are the key mediators of the tissue response to hypoxia implicated in cancer progression and metastasis (Filippopoulou et al, 2020). As oxygenation is necessary for the efficacy of treatment approaches like radiotherapy and due to the critical role played by hypoxia in the promotion of resistance in all types of solid tumors, strategies are required to reduce the demands from tumor cells on the oxygen available within the TME (Mudassar et al, 2020).…”