VIEW Open Access the Role of Ubiquitination and Deubiquitination in Cancer Metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1*
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Sun et al. Molecular Cancer (2020) 19:146 https://doi.org/10.1186/s12943-020-01262-x REVIEW Open Access The role of ubiquitination and deubiquitination in cancer metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1* Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment. Keywords: Ubiquitination, Deubiquitination, Cancer, Metabolic reprogramming Background cells have aroused increasing attention and interest [3]. Metabolic pathways are of vital importance in proliferat- Because of the generality of metabolic alterations in can- ing cells to meet their demands of various macromole- cer cells, metabolic reprogramming is thought as hall- cules and energy [1]. Compared with normal cells, mark of cancer, providing basis for tumor diagnosis and cancer cells own malignant properties, such as increased treatment [1]. For instance, the application of 18F- proliferation rate, and reside in environments short of deoxyglucose positron emission tomography is based on oxygen and nutrient. Correspondingly, metabolic activ- tumor cells’ characteristic of increased glucose con- ities are altered in cancer cells to support their malig- sumption [4]. Inhibition of some metabolic enzymes, nant biological behaviors and to adapt to stressful such as L-lactate dehydrogenase A chain (LDH-A), have conditions, such as nutrient limitation and hypoxia [1]. been observed to regress established tumors [5, 6]. Cancer metabolism is an old field of research. Warburg Therefore, research of metabolic reprogramming is of effect observed in the 1920s provides a classical example critical importance, which might provide new opportun- of metabolic reprogramming in cancer [2]. In the past ities for cancer diagnosis and treatment. few decades, enhanced biosynthesis of macromolecules, Amongst multiple post-translational modification, pro- altered energy metabolism, and maintenance of redox tein ubiquitination is a common and important process in homeostasis have been observed to be essential features cells [7, 8]. Ubiquitination and deubiquitination have been of cancer metabolism. Altered metabolism in cancer observed to be dysregulated in various types of cancers. Genetic and epigenetic aberrations, such as mutation, * Correspondence: [email protected] amplification and deletion, can be the common causes of 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang 110004, dysregulated ubiquitination and deubiquitination in can- China cer cells [9]. Ubiquitination and deubiquitination can also Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sun et al. Molecular Cancer (2020) 19:146 Page 2 of 19 be abnormally regulated by transcriptional, translational maintenance of redox homeostasis, keeping ROS in an or posttranslational mechanisms in cancer cells, exerting appropriate level to promote tumor growth rather than oncogenic or anti-cancer roles in carcinogenesis [7, 8, 10]. inducing damage [23, 24]. In recent years, the involvement of ubiquitination and Under nutrient rich conditions, activation of mTORC1 deubiquitination in the regulation of metabolic repro- supports cancer cells growth. In periods of cellular gramming in cancer cells has received a growing body of stress, low levels of amino acids or absent ATP induces attention [11]. Given the complexity and importance of mTORC1 inhibition, which subsequently activates a both cancer metabolism and protein ubiquitination, the compensatory mechanism named autophagy [25]. Au- exact roles of protein ubiquitination and deubiquitination tophagy is a highly regulated pathway essential for cell in metabolic reprogramming are worth further studies survival in nutrient-deprived conditions, complementing and analyses. The present review will highlight the ubiqui- the classical pathways like glycolysis. Autophagy supplies tination and deubiquitination system as a regulator of can- amino acids by inducing degradation of macromolecules cer metabolism and discuss future directions focusing on and organelles in lysosome, thereby providing intracellu- the strategies to improve cancer therapy. lar amino acids supply to fuel the TCA cycle, gluconeo- genesis and protein synthesis [26]. However, the Cancer metabolism interplay between autophagy and glycolysis seems to be To satisfy nutrient and energy requirements for cells’ complex. Activation of autophagy has been observed to survival and growth, metabolic pathways are altered in enhance glycolysis [27]. Deficiency of mitophagy can in- cancer cells, which is called metabolic reprogramming duce mitochondrial dysfunctions, enhancing glycolysis [1]. Metabolic reprogramming is a highly regulated and Warburg effect [28]. Additionally, studies have process [12]. Aberrant activation of mechanistic target of found that oxidative stress induced by cancer cells can rapamycin complex 1 (mTORC1) is one of the most promote aerobic glycolysis and autophagy in cancer as- common alterations in proliferating cancer cells, playing sociated fibroblasts to obtain recycled nutrients from a key role in metabolic reprogramming [12]. Under the cancer associated fibroblasts. This phenomenon is called stimulation of amino acids, mTORC1 can be activated, “Reverse Warburg Effect” [29]. Therefore, both the ana- which subsequently exerts various biological effects by bolic pathways, such as glycolysis, and the catabolic activation of different downstream targets, such as pathways, such as autophagy, interplay with each other, hypoxia-inducible factor 1 (HIF-1) and sterol regulatory together contribute to cancer metabolism and support- element-binding protein (SREBP) [12, 13]. Proliferating ing cellular growth. Taken together, abnormal alterations cancer cells require elevated synthesis of protein, lipid of multiple signaling pathways, transcription factors and and nucleotide. Glycolysis can be upregulated by metabolic pathways synergistically lead to metabolic re- mTORC1 activation, providing more glycolytic interme- programming in cancer cells. diates for biosynthesis of these macromolecules [14]. Moreover, mTORC1 activation promotes glutamine up- Ubiquitination and deubiquitination take to maintain mitochondrial ATP production [15]. Ubiquitination is an ATP-dependent cascade process li- Fatty acids can also supply carbon to the tricarboxylic gating ubiquitin, a ubiquitously expressed protein con- acid (TCA) cycle to sustain mitochondrial function [16]. sisting of 76 amino acids, to a substrate protein [30]. PI3K-AKT signaling is the most well-known mechanism Ubiquitin-activating enzymes (E1s) initially bind to ubi- for activating mTORC1 [17]. Besides, mTORC1 can be quitin for activation, and then transfer activated ubiqui- activated or inhibited by various signaling pathways dir- tin to ubiquitin-conjugating enzymes (E2s). Ubiquitin ectly or indirectly. For instance, 5′-AMP-activated pro- ligases (E3s) finally transfer ubiquitin from E2 to sub- tein kinase (AMPK) activated by energy shortage is a strates [30]. According to the number of ubiquitin crucial inhibitor of mTORC1 [18]. What’s more, tran- attaching to one lysine residue in protein, ubiquitination scription factor c-Myc and p53 also take part in meta- is divided into monoubiquitination (single ubiquitin) and bolic reprogramming through transcriptional regulation polyubiquitination (a chain of ubiquitin) [31]. In the of metabolism-related