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Ubiquitination and Deubiquitination of MCL1 in Cancer

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Ubiquitination and Deubiquitination of MCL1 in Cancer Wu et al. Cell Death and Disease (2020) 11:556 https://doi.org/10.1038/s41419-020-02760-y Cell Death & Disease REVIEW ARTICLE Open Access Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options Xiaowei Wu 1,QingyuLuo 1 and Zhihua Liu 1 Abstract MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination- mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Facts 2. Is there a need to identify other E3 ligases or deubi- 1. MCL1 is an important antiapoptotic member of the quitinases that modulate MCL1? BCL-2 family, and the elevation of MCL1 protein level 3. Can the emerging strategy of targeting deubiquiti- leads to chemoresistance and correlates with poor prog- nases upstream of MCL1 soon be successfully applied in nosis of cancer patients. clinical practice? 2. MCL1 is an unstable protein, and its stability is 4. Is the use of a proteolysis-targeting chimera a pro- regulated by the ubiquitin–proteasome system (UPS). mising strategy to directly target MCL1 by utilizing 3. Targeting MCL1 appears to be a promising strategy the UPS? in cancer therapy, but the development of an effective inhibitor targeting MCL1 has begun only recently. Introduction 4. Targeting deubiquitinases upstream of MCL1 pro- Programmed cell death (PCD), a cell suicide process, is vides an alternative strategy for inhibiting MCL1 activity. essential for normal organ development and tissue Open questions homeostasis. However, overactivation or inactivation of 1. What are the distinctions and relationships of the the PCD cascade can lead to pathogeneses, such as Par- various E3 ligases/deubiquitinases that modulate MCL1? kinson’s disease and tumorigenesis. Apoptosis is the predominant type of PCD, whereas other types have also been discovered in recent years, such as pyroptosis1, 2 3 4 Correspondence: Zhihua Liu ([email protected]) necroptosis , parthanatos , and ferroptosis . Two distinct 1State Key Laboratory of Molecular Oncology, National Cancer Center/National pathways can lead to apoptosis, the extrinsic/cell death Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of receptor pathway and the intrinsic/mitochondrial path- Medical Sciences and Peking Union Medical College, 100021 Beijing, China 5 These authors contributed equally: Xiaowei Wu, Qingyu Luo way . In the intrinsic pathway, B cell lymphoma 2 (BCL-2) Edited by M. Agostini © 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 linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Wu et al. Cell Death and Disease (2020) 11:556 Page 2 of 11 Fig. 1 Schematic model of MCL1 protein. MCL1 contains a long N-terminal regulatory domain harboring a PEST sequence, BH1–BH4 motifs and a C-terminal transmembrane (TM) domain. The arrows indicate the sites of ubiquitination (Ub): K48-linked polyubiquitin chains (red) and K63-linked polyubiquitin chains (green). family members have been shown to have a critical role in acetate (TPA)-mediated differentiation of the ML-1 regulating apoptosis by governing proapoptotic and human myeloid leukemia cell line18. MCL1 contains two antiapoptotic intracellular signals6. Numerous studies PEST domains, four BH domains, and a C-terminal have revealed the subtle regulatory network between transmembrane (TM) domain as well as an unusually long BCL-2 family members7,8, and their dysregulation can N terminus that is not observed in other BCL-2 family lead to various diseases9,10. members19 (Fig. 1). The N terminus of MCL1 harbors Chemotherapy is one of the most widely applied treat- numerous regulatory residues responsible for caspase ments for cancer in humans, and chemoresistance is one cleavage, phosphorylation, and ubiquitination, and con- of the most severe obstacles that cancer patients face. tains a PEST motif, a characteristic sequence of rapidly Apoptosis escape is considered a hallmark of cancer11, degraded proteins20. In addition, the BH1 domain and C- contributing to the resistance of cancer cells to both terminal region from aa 303 to 350 are also important for chemotherapy12,13 and radiotherapy14. Due to the reg- the rapid degradation of MCL1, contributing to its short ulatory role of the BCL-2 family in apoptotic signaling, half-life together with the PEST sequence21. The short studies of the BCL-2 family have elucidated the MCL1 half-life distinguishes it from many other BCL-2 mechanisms underlying chemoresistance and provided homologs22, and allows cells to rapidly switch between several promising therapeutic strategies. Certainly, emer- survival and apoptotic states in response to various stress ging attempts to target BCL-2 antiapoptotic members will signals. Another characteristic of MCL1 is its distinct benefit the treatment of cancer. tissue distribution and expression patterns compared with those of other BCL-2 family members23. Role of MCL1 in the mitochondrial apoptosis Several studies have provided a relatively detailed pathway mechanism underlying the antiapoptotic function of The BCL2 family contains more than 25 proteins that MCL1. Classically, the MCL1 protein has been shown to regulate the intrinsic apoptosis pathway15. Based on their anchor itself to the cytoplasmic face of the mitochondrial structure and function, BCL-2 family members are clas- outer membrane via its C-terminal TM domain24, where sified into three groups: antiapoptotic, proapoptotic, and it structurally interacts with and sequesters proapoptotic proapoptotic BH3-only proteins. Antiapoptotic proteins to suppress mitochondrial outer membrane proteins that possess BH1-4 domains include MCL1, permeabilization (MOMP) and cytochrome c release25,26 BCL-2, BCL-W, BCL-B, BCL-XL, and BFL-1/A1; proa- (Fig. 2). Conversely, the above interactions can be antag- poptotic proteins (apoptosis effectors) harboring BH1-4 onized by BH3-only proteins, which displace BAK and domains include BAX and BAK; and proapoptotic BH3- BAX from MCL1 to activate the mitochondrial apoptosis only proteins (apoptosis activators) include BIM, BID, pathway6,27. In addition to the abovementioned classic BAD, NOXA, and PUMA16. Biochemical and structural antiapoptotic function of MCL1, maintenance of MCL1 studies have revealed that the BH1, BH2, and BH3 regions levels has been shown to be necessary to preserve mito- of antiapoptotic BCL-2 family proteins are proximal to chondrial morphology and support normal mitochondrial one another and can form a surface-associated hydro- bioenergetic activity in cardiomyocytes28,29. In addition, phobic groove, a feature allowing interaction with the an amino-terminal truncated isoform of MCL1 has been BH3 amphipathic helix of BH3-containing proapoptotic reported to be anchored to the inner mitochondrial proteins and physiological antagonization15,17. MCL1 is a membrane (IMM) and exposed to the matrix where it crucial antiapoptotic member of the BCL-2 family that retains the normal IMM structure, mitochondrial fusion, was initially identified as an immediate-early gene ATP production, membrane potential, and respiration30. expressed during the 12-O-tetra-decanoylphorbol-13- This mitochondrial matrix form of MCL1 can also Official journal of the Cell Death Differentiation Association Wu et al. Cell Death and Disease (2020) 11:556 Page 3 of 11 patients with high levels of MCL1 expression have been shown to encounter drug resistance, relapse and poor prognosis outlook. For example, in diffuse large B cell leukemia, AKT-induced aerobic glycolysis promotes MCL1 protein synthesis, thereby maintaining cell survival and resistance to BCL-2 inhibitors47. MCL1 is also fre- quently upregulated in breast cancer48, especially in drug- resistant triple-negative breast cancer (TNBC) after
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