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1
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Hlavac K, Pavelkova P, Ondrisova L, Mraz M. FoxO1 signaling in B cell malignancies and its therapeutic targeting. FEBS Lett 2024. [PMID: 39533662 DOI: 10.1002/1873-3468.15057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 10/09/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).
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Affiliation(s)
- Krystof Hlavac
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Brno, Czech Republic
| | - Petra Pavelkova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Brno, Czech Republic
| | - Laura Ondrisova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Brno, Czech Republic
| | - Marek Mraz
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Brno, Czech Republic
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2
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Kang D, Yang MJ, Cheong HK, Park CJ. NMR investigation of FOXO4-DNA interaction for discriminating target and non-target DNA sequences. Commun Biol 2024; 7:1425. [PMID: 39487330 PMCID: PMC11530643 DOI: 10.1038/s42003-024-07133-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/24/2024] [Indexed: 11/04/2024] Open
Abstract
Forkhead box O4 (FOXO4), a human transcription factor, recognizes target DNA through its forkhead domain (FHD) while maintaining comparable binding affinity to non-target DNA. The conserved region 3 (CR3), a transactivation domain, modulates DNA binding kinetics to FHD and contributes to target DNA selection, but the underlying mechanism of this selection remains elusive. Using paramagnetic relaxation enhancement analysis, we observed a minor state of CR3 close to FHD in the presence of non-target DNA, a state absent when FHD interacts with target DNA. This minor state suggests that CR3 effectively masks the non-target DNA-binding interface on FHD. The interaction weakens significantly under high salt concentration, implying that CR3 or high salt concentrations can modulate electrostatic interactions with non-target DNA. Our 15N relaxation measurements revealed FHD's flexibility with non-target DNA and increased rigidity with target DNA binding. Our findings offer insights into the role of FOXO4 as a transcription initiator.
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Affiliation(s)
- Donghoon Kang
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Min June Yang
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea
| | - Hae-Kap Cheong
- Ochang Center, Korea Basic Science Institute, Chungcheongbuk-do, 28119, Republic of Korea
| | - Chin-Ju Park
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, 61005, Republic of Korea.
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3
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Wang W, Albadari N, Du Y, Fowler JF, Sang HT, Xian W, McKeon F, Li W, Zhou J, Zhang R. MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future. Pharmacol Rev 2024; 76:414-453. [PMID: 38697854 PMCID: PMC11068841 DOI: 10.1124/pharmrev.123.001026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/28/2023] [Accepted: 01/16/2024] [Indexed: 05/05/2024] Open
Abstract
Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM2's activities extend from carcinogenesis to immunity to the response to various cancer therapies. Since the report of the first MDM2 inhibitor more than 30 years ago, various approaches to inhibit MDM2 have been attempted, with hundreds of small-molecule inhibitors evaluated in preclinical studies and numerous molecules tested in clinical trials. Although many MDM2 inhibitors and degraders have been evaluated in clinical trials, there is currently no Food and Drug Administration (FDA)-approved MDM2 inhibitor on the market. Nevertheless, there are several current clinical trials of promising agents that may overcome the past failures, including agents granted FDA orphan drug or fast-track status. We herein summarize the research efforts to discover and develop MDM2 inhibitors, focusing on those that induce MDM2 degradation and exert anticancer activity, regardless of the p53 status of the cancer. We also describe how preclinical and clinical investigations have moved toward combining MDM2 inhibitors with other agents, including immune checkpoint inhibitors. Finally, we discuss the current challenges and future directions to accelerate the clinical application of MDM2 inhibitors. In conclusion, targeting MDM2 remains a promising treatment approach, and targeting MDM2 for protein degradation represents a novel strategy to downregulate MDM2 without the side effects of the existing agents blocking p53-MDM2 binding. Additional preclinical and clinical investigations are needed to finally realize the full potential of MDM2 inhibition in treating cancer and other chronic diseases where MDM2 has been implicated. SIGNIFICANCE STATEMENT: Overexpression/amplification of the MDM2 oncogene has been detected in various human cancers and is associated with disease progression, treatment resistance, and poor patient outcomes. This article reviews the previous, current, and emerging MDM2-targeted therapies and summarizes the preclinical and clinical studies combining MDM2 inhibitors with chemotherapy and immunotherapy regimens. The findings of these contemporary studies may lead to safer and more effective treatments for patients with cancers overexpressing MDM2.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Najah Albadari
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Yi Du
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Josef F Fowler
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Hannah T Sang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wa Xian
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Frank McKeon
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Wei Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Jia Zhou
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (W.W., Y.D., J.F.F., H.T.S., R.Z.), Drug Discovery Institute (W.W., R.Z.), Stem Cell Center, Department of Biology and Biochemistry (W.X., F.M.), University of Houston, Houston, Texas; College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee (N.A., W.L.); and Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (J.Z.)
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Cheng M, Nie Y, Song M, Chen F, Yu Y. Forkhead box O proteins: steering the course of stem cell fate. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:7. [PMID: 38466341 DOI: 10.1186/s13619-024-00190-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 02/26/2024] [Indexed: 03/13/2024]
Abstract
Stem cells are pivotal players in the intricate dance of embryonic development, tissue maintenance, and regeneration. Their behavior is delicately balanced between maintaining their pluripotency and differentiating as needed. Disruptions in this balance can lead to a spectrum of diseases, underscoring the importance of unraveling the complex molecular mechanisms that govern stem cell fate. Forkhead box O (FOXO) proteins, a family of transcription factors, are at the heart of this intricate regulation, influencing a myriad of cellular processes such as survival, metabolism, and DNA repair. Their multifaceted role in steering the destiny of stem cells is evident, as they wield influence over self-renewal, quiescence, and lineage-specific differentiation in both embryonic and adult stem cells. This review delves into the structural and regulatory intricacies of FOXO transcription factors, shedding light on their pivotal roles in shaping the fate of stem cells. By providing insights into the specific functions of FOXO in determining stem cell fate, this review aims to pave the way for targeted interventions that could modulate stem cell behavior and potentially revolutionize the treatment and prevention of diseases.
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Affiliation(s)
- Mengdi Cheng
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Yujie Nie
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Min Song
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
| | - Fulin Chen
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China
- Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi'an, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China
| | - Yuan Yu
- Laboratory of Tissue Engineering, College of Life Sciences, Northwest University, Xi'an, China.
- Provincial Key Laboratory of Biotechnology of Shaanxi, Northwest University, Xi'an, China.
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi'an, China.
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Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol 2024; 25:46-64. [PMID: 37710009 DOI: 10.1038/s41580-023-00649-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2023] [Indexed: 09/16/2023]
Abstract
The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.
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Affiliation(s)
| | - Tobias B Dansen
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Boudewijn M T Burgering
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
- Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
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6
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Guo M, Xiong Y. Sex-biased genome-editing effects of CRISPR-Cas9 across cancer cells dependent on p53 status. iScience 2023; 26:107529. [PMID: 37636042 PMCID: PMC10448110 DOI: 10.1016/j.isci.2023.107529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 06/12/2023] [Accepted: 07/28/2023] [Indexed: 08/29/2023] Open
Abstract
The CRISPR-Cas9 system has emerged as the dominant technology for gene editing and clinical applications. One major concern is its off-target effect after the introduction of exogenous CRISPR-Cas9 into cells. Several previous studies have investigated either Cas9 alone or CRISPR-Cas9 interactions with p53. Here, we reanalyzed previously reported data of p53-associated Cas9 activities and observed large significant sex differences between p53-wildtype and p53-mutant cells. To expand the impact of this finding, we further examined all protein-coding genes for sex-specific dependencies in a large-scale CRISPR-Cas9 screening dataset from the DepMap project. We highlighted the p53-dependent sex bias of gene knockouts (including MYC, PIK3CA, KAT2B, KDM4E, SUV39H1, FANCB, TLR7, and APC2) across cancer types and potential mechanisms (mediated by transcriptional factors, including SOX9, FOXO4, LEF1, and RYBP) underlying this phenomenon. Our results suggest that the p53-dependent sex bias may need to be considered in future clinical applications of CRISPR-Cas9, especially in cancer.
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Affiliation(s)
- Mengbiao Guo
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Yuanyan Xiong
- Key Laboratory of Gene Engineering of the Ministry of Education, Institute of Healthy Aging Research, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
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7
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Yang Y, Ma Y, Li M, Zhu H, Shi P, An R. STUB1 directs FOXQ1-mediated transactivation of Ldha gene and facilitates lactate production in mouse Sertoli cells. Cell Tissue Res 2023; 392:565-579. [PMID: 36575252 DOI: 10.1007/s00441-022-03705-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/06/2022] [Indexed: 12/29/2022]
Abstract
Sertoli cells (SCs) preferentially use glucose to convert to lactate. As an energy source, lactate is essential for survival of developed germ cells (GCs) due to its anti-apoptotic effect. Failure to maintain lactate metabolism homeostasis leads to infertility or germ cell apoptosis. Several Sertoli cell-expressed genes, such as Foxq1 and Gata4, have been identified as critical regulators for lactate synthesis, but the pathways that potentially modulate their expression remain ill defined. Although recent work from our collaborators pointed to an involvement of STIP1 homology and U-box-containing protein 1 (STUB1) in the modulation of Sertoli cell response to GCs-derived IL-1α, a true physiological function of STUB1 signaling in SCs has not been demonstrated. We therefore conditionally ablated Stub1 in SCs using Amh-Cre. Stub1 knockout males exhibited impaired fertility due to oligozoospermia and asthenospermia, possibly caused by lactate deficiency. Furthermore, by means of chromatin immunoprecipitation, in vivo ubiquitination, and luciferase reporter assays, we showed that STUB1 directed forkhead box Q1 (FOXQ1)-mediated transactivation of the lactate dehydrogenase A (Ldha) gene via K63-linked non-proteolytic polyubiquitination, thus facilitating lactate production in follicle-stimulating hormone (FSH)-stimulated SCs. In agreement, overexpression of LDHA by lentivirus infection effectively rescued the lactate production in TM4Stub1-/- cells. Our results collectively identify STUB1-mediated transactivation of FOXQ1 signaling as a post-translationally modified transcriptional regulatory network underlying nursery function in SCs, which may nutritionally contribute to Sertoli cell dysfunction of male infertility.
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Affiliation(s)
- Yang Yang
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an 710061, Shaanxi, People's Republic of China
- Reproductive Medicine Center, Xi'an People's Hospital (Xi'an NO.4 Hospital), 710004, Shaanxi, People's Republic of China
| | - Yuan Ma
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi'an 710038, Shaanxi, People's Republic of China
| | - Mao Li
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi'an 710038, Shaanxi, People's Republic of China
| | - Hongli Zhu
- Reproductive Medicine Center, Xi'an People's Hospital (Xi'an NO.4 Hospital), 710004, Shaanxi, People's Republic of China
| | - Panpan Shi
- Reproductive Medicine Center, Xi'an People's Hospital (Xi'an NO.4 Hospital), 710004, Shaanxi, People's Republic of China
| | - Ruifang An
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an 710061, Shaanxi, People's Republic of China.
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Saha G, Roy S, Basu M, Ghosh MK. USP7 - a crucial regulator of cancer hallmarks. Biochim Biophys Acta Rev Cancer 2023; 1878:188903. [PMID: 37127084 DOI: 10.1016/j.bbcan.2023.188903] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 04/28/2023] [Accepted: 04/28/2023] [Indexed: 05/03/2023]
Abstract
Over the course of three decades of study, the deubiquitinase Herpesvirus associated Ubiquitin-Specific Protease/Ubiquitin-Specific Protease 7 (HAUSP/USP7) has gradually come to be recognized as a crucially important molecule in cellular physiology. The fact that USP7 is overexpressed in a number of cancers, including breast, prostate, colorectal, and lung cancers, supports the idea that USP7 is also an important regulator of tumorigenesis. In this review, we discuss USP7's function in relation to the cancer hallmarks described by Hanahan and Weinberg. This post-translational modifier can support increased proliferation, block unfavorable growth signals, stop cell death, and support an unstable cellular genome by manipulating key players in the pertinent signalling circuit. It is interesting to note that USP7 also aids in the stabilization of molecules that support angiogenesis and metastasis. Targeting USP7 has now emerged as a crucial component of USP7 research because pharmacological inhibition of USP7 supports p53-mediated cell cycle arrest and apoptosis. Efficacious USP7 inhibition is currently being investigated in both synthetic and natural compounds, but issues with selectivity and a lack of co-crystal structure have hindered USP7 inhibition from being tested in clinical settings. Moreover, the development of new, more effective USP7 inhibitors and their encouraging implications by numerous groups give us a glimmer of hope for USP7-targeting medications as effective substitutes for hazardous cancer chemotherapeutics.
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Affiliation(s)
- Gouranga Saha
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India
| | - Srija Roy
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India
| | - Malini Basu
- Department of Microbiology, Dhruba Chand Halder College, University of Calcutta, Kolkata, PIN - 743372, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata-700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, PIN - 700032, India.
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9
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Rani M, Kumari R, Singh SP, Devi A, Bansal P, Siddiqi A, Alsahli MA, Almatroodi SA, Rahmani AH, Rizvi MMA. MicroRNAs as master regulators of FOXO transcription factors in cancer management. Life Sci 2023; 321:121535. [PMID: 36906255 DOI: 10.1016/j.lfs.2023.121535] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/19/2023] [Accepted: 02/23/2023] [Indexed: 03/12/2023]
Abstract
MicroRNAs are critical regulators of the plethora of genes, including FOXO "forkhead" dependent transcription factors, which are bonafide tumour suppressors. The FOXO family members modulate a hub of cellular processes like apoptosis, cell cycle arrest, differentiation, ROS detoxification, and longevity. Aberrant expression of FOXOs in human cancers has been observed due to their down-regulation by diverse microRNAs, which are predominantly involved in tumour initiation, chemo-resistance and tumour progression. Chemo-resistance is a major obstacle in cancer treatment. Over 90% of casualties in cancer patients are reportedly associated with chemo-resistance. Here, we have primarily discussed the structure, functions of FOXO and also their post-translational modifications which influence the activities of these FOXO family members. Further, we have addressed the role of microRNAs in carcinogenesis by regulating the FOXOs at post-transcriptional level. Therefore, microRNAs-FOXO axis can be exploited as a novel cancer therapy. The administration of microRNA-based cancer therapy is likely to be beneficial to curb chemo-resistance in cancers.
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Affiliation(s)
- Madhu Rani
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Rashmi Kumari
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Shashi Prakash Singh
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India; Centre for Pharmacology and Therapeutics, Rosewell Park Comprehensive Care Centre, 665 Elm Street, Buffalo, NY, USA 14203
| | - Annu Devi
- Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India
| | - Preeti Bansal
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Aisha Siddiqi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - Saleh A Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Buraydah 51452, Saudi Arabia
| | - M Moshahid Alam Rizvi
- Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
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Kozai K, Moreno-Irusta A, Iqbal K, Winchester ML, Scott RL, Simon ME, Muto M, Parrish MR, Soares MJ. The AKT1-FOXO4 axis reciprocally regulates hemochorial placentation. Development 2023; 150:dev201095. [PMID: 36607602 PMCID: PMC10110493 DOI: 10.1242/dev.201095] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/21/2022] [Indexed: 01/07/2023]
Abstract
Hemochorial placentation involves the differentiation of invasive trophoblast cells, specialized cells that possess the capacity to exit the placenta and invade into the uterus where they restructure the vasculature. Invasive trophoblast cells arise from a well-defined compartment within the placenta, referred to as the junctional zone in rat and the extravillous trophoblast cell column in human. In this study, we investigated roles for AKT1, a serine/threonine kinase, in placental development using a genome-edited/loss-of-function rat model. Disruption of AKT1 resulted in placental, fetal and postnatal growth restriction. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone and in invasive trophoblast cells of the rat placentation site. Foxo4 gene disruption using genome editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells, but in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network that reciprocally controls critical indices of hemochorial placenta development.
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Affiliation(s)
- Keisuke Kozai
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Ayelen Moreno-Irusta
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Khursheed Iqbal
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Mae-Lan Winchester
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Regan L. Scott
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Mikaela E. Simon
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Masanaga Muto
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Marc R. Parrish
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Michael J. Soares
- Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Center for Perinatal Research, Children's Mercy Research Institute, Children's Mercy, Kansas City, MO 64108, USA
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11
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Gui T, Burgering BMT. FOXOs: masters of the equilibrium. FEBS J 2022; 289:7918-7939. [PMID: 34610198 PMCID: PMC10078705 DOI: 10.1111/febs.16221] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 09/22/2021] [Accepted: 10/04/2021] [Indexed: 01/14/2023]
Abstract
Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post-translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences.
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Affiliation(s)
- Tianshu Gui
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
| | - Boudewijn M T Burgering
- Molecular Cancer Research, Center Molecular Medicine, University Medical Center Utrecht and the Oncode Institute, The Netherlands
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12
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Marchelek-Mysliwiec M, Nalewajska M, Turoń-Skrzypińska A, Kotrych K, Dziedziejko V, Sulikowski T, Pawlik A. The Role of Forkhead Box O in Pathogenesis and Therapy of Diabetes Mellitus. Int J Mol Sci 2022; 23:ijms231911611. [PMID: 36232910 PMCID: PMC9569915 DOI: 10.3390/ijms231911611] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/19/2022] [Accepted: 09/28/2022] [Indexed: 11/16/2022] Open
Abstract
Type 2 diabetes is a disease that causes numerous complications disrupting the functioning of the entire body. Therefore, new treatments for the disease are being sought. Studies in recent years have shown that forkhead box O (FOXO) proteins may be a promising target for diabetes therapy. FOXO proteins are transcription factors involved in numerous physiological processes and in various pathological conditions, including cardiovascular diseases and diabetes. Their roles include regulating the cell cycle, DNA repair, influencing apoptosis, glucose metabolism, autophagy processes and ageing. FOXO1 is an important regulator of pancreatic beta-cell function affecting pancreatic beta cells under conditions of insulin resistance. FOXO1 also protects beta cells from damage resulting from oxidative stress associated with glucose and lipid overload. FOXO has been shown to affect a number of processes involved in the development of diabetes and its complications. FOXO regulates pancreatic β-cell function during metabolic stress and also plays an important role in regulating wound healing. Therefore, the pharmacological regulation of FOXO proteins is a promising approach to developing treatments for many diseases, including diabetes mellitus. In this review, we describe the role of FOXO proteins in the pathogenesis of diabetes and the role of the modulation of FOXO function in the therapy of this disease.
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Affiliation(s)
| | - Magdalena Nalewajska
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Agnieszka Turoń-Skrzypińska
- Department of Medical Rehabilitation and Clinical Rehabilitation, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Katarzyna Kotrych
- Department of Radiology, West Pomeranian Center of Oncology, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Violetta Dziedziejko
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Tadeusz Sulikowski
- Department of General, Minimally Invasive, and Gastroenterological Surgery, Pomeranian Medical University, 70-204 Szczecin, Poland
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-204 Szczecin, Poland
- Correspondence:
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13
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Han R, Huang H, Xia W, Liu J, Luo H, Tang J, Xia Z. Perspectives for Forkhead box transcription factors in diabetic cardiomyopathy: Their therapeutic potential and possible effects of salvianolic acids. Front Cardiovasc Med 2022; 9:951597. [PMID: 36035917 PMCID: PMC9403618 DOI: 10.3389/fcvm.2022.951597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/27/2022] [Indexed: 11/15/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is the primary cause of morbidity and mortality in diabetic cardiovascular complications, which initially manifests as cardiac hypertrophy, myocardial fibrosis, dysfunctional remodeling, and diastolic dysfunction, followed by systolic dysfunction, and eventually end with acute heart failure. Molecular mechanisms underlying these pathological changes in diabetic hearts are complicated and multifactorial, including but not limited to insulin resistance, oxidative stress, lipotoxicity, cardiomyocytes apoptosis or autophagy, inflammatory response, and myocardial metabolic dysfunction. With the development of molecular biology technology, accumulating evidence illustrates that members of the class O of Forkhead box (FoxO) transcription factors are vital for maintaining cardiomyocyte metabolism and cell survival, and the functions of the FoxO family proteins can be modulated by a wide variety of post-translational modifications including phosphorylation, acetylation, ubiquitination, arginine methylation, and O-glycosylation. In this review, we highlight and summarize the most recent advances in two members of the FoxO family (predominately FoxO1 and FoxO3a) that are abundantly expressed in cardiac tissue and whose levels of gene and protein expressions change as DCM progresses, with the goal of providing valuable insights into the pathogenesis of diabetic cardiovascular complications and discussing their therapeutic potential and possible effects of salvianolic acids, a natural product.
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Affiliation(s)
- Ronghui Han
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hemeng Huang
- Department of Emergency, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Weiyi Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- Department of Orthopaedics and Traumatology, The Univerisity of Hong Kong, Hong Kong, China
- *Correspondence: Weiyi Xia,
| | - Jingjin Liu
- Department of Cardiology, Shenzhen People’s Hospital and The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, China
| | - Hui Luo
- Marine Biomedical Research Institution, Guangdong Medical University, Zhanjiang, China
| | - Jing Tang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhengyuan Xia
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, The University of Hong Kong, Hong Kong, China
- Zhengyuan Xia,
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14
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The FOXO family of transcription factors: key molecular players in gastric cancer. J Mol Med (Berl) 2022; 100:997-1015. [PMID: 35680690 DOI: 10.1007/s00109-022-02219-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/19/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
Gastric cancer (GC) is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death with an oncological origin. Despite its decline in incidence and mortality in recent years, GC remains a global public problem that seriously threatens patients' health and lives. The forkhead box O proteins (FOXOs) are a family of evolutionarily conserved transcription factors (TFs) with crucial roles in cell fate decisions. In mammals, the FOXO family consists of four members FOXO1, 3a, 4, and 6. FOXOs play crucial roles in a variety of biological processes, such as development, metabolism, and stem cell maintenance, by regulating the expression of their target genes in space and time. An accumulating amount of evidence has shown that the dysregulation of FOXOs is involved in GC progression by affecting multiple cellular processes, including proliferation, apoptosis, invasion, metastasis, cell cycle progression, carcinogenesis, and resistance to chemotherapeutic drugs. In this review, we systematically summarize the recent findings on the regulatory mechanisms of FOXO family expression and activity and elucidate its roles in GC progression. Moreover, we also highlight the clinical implications of FOXOs in GC treatment.
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15
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Lee SH, Jung S, Lee YJ, Hyun M, Chung KC. FBXO7 triggers caspase 8-mediated proteolysis of the transcription factor FOXO4 and exacerbates neuronal cytotoxicity. J Biol Chem 2021; 297:101426. [PMID: 34800438 PMCID: PMC8665361 DOI: 10.1016/j.jbc.2021.101426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 11/05/2021] [Accepted: 11/15/2021] [Indexed: 01/26/2023] Open
Abstract
Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene (Fbxo7) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8-knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.
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Affiliation(s)
- Su Hyoun Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Sungyeon Jung
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Yun Ju Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Minju Hyun
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Kwang Chul Chung
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
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16
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Du S, Zheng H. Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases. Cell Biosci 2021; 11:188. [PMID: 34727995 PMCID: PMC8561869 DOI: 10.1186/s13578-021-00700-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 10/20/2021] [Indexed: 12/18/2022] Open
Abstract
Aging happens to all of us as we live. Thanks to the improved living standard and discovery of life-saving medicines, our life expectancy has increased substantially across the world in the past century. However, the rise in lifespan leads to unprecedented increases in both the number and the percentage of individuals 65 years and older, accompanied by the increased incidences of age-related diseases such as type 2 diabetes mellitus and Alzheimer's disease. FoxO transcription factors are evolutionarily conserved molecules that play critical roles in diverse biological processes, in particular aging and metabolism. Their dysfunction is often found in the pathogenesis of many age-related diseases. Here, we summarize the signaling pathways and cellular functions of FoxO proteins. We also review the complex role of FoxO in aging and age-related diseases, with focus on type 2 diabetes and Alzheimer's disease and discuss the possibility of FoxO as a molecular link between aging and disease risks.
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Affiliation(s)
- Shuqi Du
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA
| | - Hui Zheng
- Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
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17
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Chen YH, Li CL, Chen WJ, Liu J, Wu HT. Diverse roles of FOXO family members in gastric cancer. World J Gastrointest Oncol 2021; 13:1367-1382. [PMID: 34721771 PMCID: PMC8529928 DOI: 10.4251/wjgo.v13.i10.1367] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fifth most diagnosed cancer and the third leading cause of cancer-related death worldwide. Although progress has been made in diagnosis, surgical resection, systemic chemotherapy, and immunotherapy, patients with GC still have a poor prognosis. The overall 5-year survival rate in patients with advanced GC is less than 5%. The FOXO subfamily, of the forkhead box family of transcription factors, consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6. This subfamily plays an important role in many cellular processes, such as cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism, in both normal tissue and malignant tumors. Various studies support a role for FOXOs as tumor suppressors based on their ability to inhibit angiogenesis and metastasis, and promote apoptosis, yet several other studies have shown that FOXOs might also promote tumor progression in certain circumstances. To elucidate the diverse roles of FOXOs in GC, this article systematically reviews the cellular functions of FOXOs in GC to determine potential therapeutic targets and treatment strategies for patients with GC.
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Affiliation(s)
- Yu-Han Chen
- Department of Clinical Medicine, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Chun-Lan Li
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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18
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Oli V, Gupta R, Kumar P. FOXO and related transcription factors binding elements in the regulation of neurodegenerative disorders. J Chem Neuroanat 2021; 116:102012. [PMID: 34400291 DOI: 10.1016/j.jchemneu.2021.102012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/16/2021] [Accepted: 08/07/2021] [Indexed: 12/16/2022]
Abstract
Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and others, are characterized by progressive loss of neuronal cells, which causes memory impairment and cognitive decline. Mounting evidence demonstrated the possible implications of diverse biological processes, namely oxidative stress, mitochondrial dysfunction, aberrant cell cycle re-entry, post-translational modifications, protein aggregation, impaired proteasome dysfunction, autophagy, and many others that cause neuronal cell death. The condition worsens as there is no effective treatment for such diseases due to their complex pathogenesis and mechanism. Mounting evidence demonstrated the role of regulatory transcription factors, such as NFκβ, FoxO, Myc, CREB, and others that regulate the biological processes and diminish the disease progression and pathogenesis. Studies demonstrated that forkhead box O (FoxO) transcription factors had been implicated in the regulation of aging and longevity. Further, the functions of FoxO proteins are regulated by different post-translational modifications (PTMs), namely acetylation, and ubiquitination. Various studies concluded that FoxO proteins exert both neuroprotective and neurotoxic properties depending on their regulation mechanism and activity in the brain. Thus, understanding the nature of FoxO expression and activity in the brain will help develop effective therapeutic strategies. Herein, firstly, we discuss the role of FoxO protein in cell cycle regulation and cell proliferation, followed by the regulation of FoxO proteins through acetylation and ubiquitination. We also briefly explain the activity and expression pattern of FoxO proteins in the neuronal cells and explain the mechanism through which FoxO proteins are rescued from oxidative stress-induced neurotoxicity. Later on, we present a detailed view of the implication of FoxO proteins in neurodegenerative disease and FoxO proteins as an effective therapeutic target.
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Affiliation(s)
- Vaibhav Oli
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly Delhi College of Engineering), India.
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19
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Rana T, Behl T, Sehgal A, Mehta V, Singh S, Sharma N, Bungau S. Elucidating the Possible Role of FoxO in Depression. Neurochem Res 2021; 46:2761-2775. [PMID: 34075521 DOI: 10.1007/s11064-021-03364-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 12/21/2022]
Abstract
Forkhead box-O (FoxO) transcriptional factors perform essential functions in several physiological and biological processes. Recent studies have shown that FoxO is implicated in the pathophysiology of depression. Changes in the upstream mediators of FoxOs including brain-derived neurotrophic factor (BDNF) and protein kinase B have been associated with depressive disorder and the antidepressant agents are known to alter the phosphorylation of FoxOs. Moreover, FoxOs might be regulated by serotonin or noradrenaline signaling and the hypothalamic-pituitary-adrenal (HPA)-axis,both of them are associated with the development of the depressive disorder. FoxO also regulates neural morphology, synaptogenesis, and neurogenesis in the hippocampus, which accounts for the pathogenesis of the depressive disorder. The current article underlined the potential functions of FoxOs in the etiology of depressive disorder and formulate few essential proposals for further investigation. The review also proposes that FoxO and its signal pathway might establish possible therapeutic mediators for the management of depressive disorder.
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Affiliation(s)
- Tarapati Rana
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India.,Government Pharmacy College, Seraj, Mandi, Himachal Pradesh, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India.
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Vineet Mehta
- Government College of Pharmacy, Rohru, Distt., Shimla, Himachal Pradesh, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Chandigarh, Punjab, India
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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20
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Yang S, Pang L, Dai W, Wu S, Ren T, Duan Y, Zheng Y, Bi S, Zhang X, Kong J. Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review). Front Oncol 2021; 11:667730. [PMID: 34123834 PMCID: PMC8190381 DOI: 10.3389/fonc.2021.667730] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/28/2021] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.
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Affiliation(s)
- Shaojie Yang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Liwei Pang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wanlin Dai
- Innovation Institute of China Medical University, Shenyang, China
| | - Shuodong Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tengqi Ren
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yunlong Duan
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yuting Zheng
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Shiyuan Bi
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaolin Zhang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing Kong
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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21
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Shi YY, Meng XT, Xu YN, Tian XJ. Role of FOXO protein's abnormal activation through PI3K/AKT pathway in platinum resistance of ovarian cancer. J Obstet Gynaecol Res 2021; 47:1946-1957. [PMID: 33827148 DOI: 10.1111/jog.14753] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 02/04/2021] [Accepted: 03/05/2021] [Indexed: 01/12/2023]
Abstract
AIM Platinum-based chemotherapy is the standard treatment for ovarian cancer. However, tumor cells' resistance to platinum drugs often occurs. This paper provides a review of Forkhead box O (FOXO) protein's role in platinum resistance of ovarian cancer which hopefully may provide some further guidance for the treatment of platinum-resistant ovarian cancer. METHODS We reviewed a 128 published papers from authoritative and professional journals on FOXO and platinum-resistant ovarian cancer, and adopts qualitative analyses and interpretation based on the literature. RESULTS Ovarian cancer often has abnormal activation of cellular pathways, the most important of which is the PI3K/AKT pathway. FOXOs act as crucial downstream factor of the PI3K/Akt pathway and are negatively regulated by it. DNA damage response and apoptosis including the relationship between FOXOs and ATM-Chk2-p53 are essential for platinum resistance of ovarian cancer. Through gene expression analysis in platinum-resistant ovarian cancer cell model, it was found that FoxO-1 is decreased in platinum-resistant ovarian cancer, so studying the role of FOXO in the pathway on platinum-induced apoptosis may further guide the treatment of platinum-resistant ovarian cancer. CONCLUSIONS There are many drug resistance mechanisms in ovarian cancer, wherein the decrease in cancer cells apoptosis is one of the important causes. Constituted by a series of transcription factors evolving conservatively and mainly working in inhibiting cancer, FOXO proteins play various roles in cells' antitumor response. More and more evidence suggests that we need to re-understand the role that FOXOs have played in cancer development and treatment.
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Affiliation(s)
- Yun-Yue Shi
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiang-Tian Meng
- Department of Ophthalmology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ya-Nan Xu
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiu-Juan Tian
- Department of Obstetrics and gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin Province, China
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22
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Kim J, Ahn D, Park CJ. FOXO4 Transactivation Domain Interaction with Forkhead DNA Binding Domain and Effect on Selective DNA Recognition for Transcription Initiation. J Mol Biol 2021; 433:166808. [PMID: 33450250 DOI: 10.1016/j.jmb.2021.166808] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 11/25/2022]
Abstract
Forkhead box O4 (FOXO4) is a human transcription factor (TF) that participates in cell homeostasis. While the structure and DNA binding properties of the conserved forkhead domain (FHD) have been thoroughly investigated, how the transactivation domain (TAD) regulates the DNA binding properties of the protein remains elusive. Here, we investigated the role of TAD in modulating the DNA binding properties of FOXO4 using solution NMR. We found that TAD and FHD form an intramolecular complex mainly governed by hydrophobic interaction. Remarkably, TAD and DNA share the same surface of FHD for binding. While FHD did not differentiate binding to target and non-target DNA, the FHD-TAD complex showed different behaviors depending on the DNA sequence. In the presence of TAD, free and DNA-bound FHD exhibited a slow exchange with target DNA and a fast exchange with non-target DNA. The interaction of the two domains affected the kinetic function of FHD depending on the type of DNA. Based on these findings, we suggest a transcription initiation model by which TAD modulates FOXO4 recognition of its target promoter DNA sequences. This study describes the function of TAD in FOXO4 and provides a new kinetic perspective on target sequence selection by TFs.
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Affiliation(s)
- Jinwoo Kim
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, South Korea
| | - Dabin Ahn
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, South Korea
| | - Chin-Ju Park
- Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, South Korea.
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23
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Choi HH, Zou S, Wu J, Wang H, Phan L, Li K, Zhang P, Chen D, Liu Q, Qin B, Nguyen TAT, Yeung SJ, Fang L, Lee M. EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:2000681. [PMID: 33101846 PMCID: PMC7578864 DOI: 10.1002/advs.202000681] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/19/2020] [Indexed: 05/10/2023]
Abstract
Forkhead-Box Class O 4 (FOXO4) is involved in critical biological functions, but its response to EGF-PKB/Akt signal regulation is not well characterized. Here, it is reported that FOXO4 levels are downregulated in response to EGF treatment, with concurrent elevation of COP9 Signalosome subunit 6 (CSN6) and E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1) levels. Mechanistic studies show that CSN6 binds and regulates FOXO4 stability through enhancing the E3 ligase activity of COP1, and that COP1 directly interacts with FOXO4 through a VP motif on FOXO4 and accelerates the ubiquitin-mediated degradation of FOXO4. Metabolomic studies demonstrate that CSN6 expression leads to serine and glycine production. It is shown that FOXO4 directly binds and suppresses the promoters of serine-glycine-one-carbon (SGOC) pathway genes, thereby diminishing SGOC metabolism. Evidence shows that CSN6 can regulate FOXO4-mediated SGOC gene expression. Thus, these data suggest a link of CSN6-FOXO4 axis and ser/gly metabolism. Further, it is shown that CSN6-COP1-FOXO4 axis is deregulated in cancer and that the protein expression levels of CSN6 and FOXO4 can serve as prognostic markers for cancers. The results illustrate a pathway regulation of FOXO4-mediated serine/glycine metabolism through the function of CSN6-COP1 axis. Insights into this pathway may be strategically designed for therapeutic intervention in cancers.
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Affiliation(s)
- Hyun Ho Choi
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Shaomin Zou
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Jian‐lin Wu
- State Key Laboratory of Quality Research in Chinese MedicineMacau Institute for Applied Research in Medicine and HealthMacau University of Science and TechnologyMacao999078China
| | - Huashe Wang
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Liem Phan
- Department of Molecular and Cellular OncologyDivision of Basic Science ResearchThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Kai Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Peng Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Daici Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Qingxin Liu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Baifu Qin
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | | | - Sai‐Ching J. Yeung
- Department of Emergency MedicineDivision of Internal MedicineThe University of Texas MD Anderson Cancer CenterHoustonTX77030USA
| | - Lekun Fang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Department of Colorectal SurgeryThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
| | - Mong‐Hong Lee
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseaseThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
- Guangdong Research Institute of GastroenterologyThe Sixth Affiliated HospitalSun Yat‐sen UniversityGuangzhou510655China
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24
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Halim A, Liu L, Ariyanti AD, Ju Y, Luo Q, Song G. Low-dose suspended graphene oxide nanosheets induce antioxidant response and osteogenic differentiation of bone marrow-derived mesenchymal stem cells via JNK-dependent FoxO1 activation. J Mater Chem B 2020; 7:5998-6009. [PMID: 31538158 DOI: 10.1039/c9tb01413f] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Large bone defects caused by bone-related diseases and traumatic injuries can disrupt the self-healing potential of bone tissue. Mesenchymal stem cells (MSCs) are known as promising cell sources for bone tissue regeneration. Graphene oxide (GO), a derivative of graphene, has been recently used for controlling the differentiation of stem cells towards bone-forming cells. However, the effect of GO on the intracellular redox system in MSCs is still unknown. In this study, we found that low-dose GO nanosheets (0.1 μg mL-1) did not affect the viability and slightly increased the proliferation of BM-MSCs. Moreover, they could also maintain the redox balance by upregulating the antioxidant genes such as MnSOD and catalase during osteogenic differentiation. The osteoinductive and antioxidative effects of the low-dose GO nanosheets were regulated by the activation and nuclear localization of FoxO1, and its activation was dependent on the JNK activity. The blockade of JNK activity by SP600125 inhibited the nuclear translocation of FoxO1, and subsequently suppressed the osteogenic differentiation and antioxidant defense system of BM-MSCs. Overall, our results show that the osteoinductive and antioxidative effects of low-dose GO nanosheets occur through the activation of the JNK and FoxO1 signaling pathways.
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Affiliation(s)
- Alexander Halim
- Key Laboratory of Biorheological Science & Technology, Ministry of Education, College of Bioengineering, Chongqing University, 174 Shazheng Street, Shapingba, Chongqing 400030, China.
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25
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Zheng H, Yang G, Fu J, Chen Z, Yuan G. Mdm2 Promotes Odontoblast-like Differentiation by Ubiquitinating Dlx3 and p53. J Dent Res 2020; 99:320-328. [PMID: 31847675 DOI: 10.1177/0022034519893672] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Dentin is an important structural component of the tooth. Odontoblast differentiation is an essential biological process that guarantees normal dentin formation, which is precisely regulated by various proteins. Murine double minute 2 (Mdm2) is an E3 ubiquitin ligase, and it plays a pivotal role in the differentiation of different cell types, such as osteoblasts and myoblasts. However, whether Mdm2 plays a role in odontoblast differentiation remains unknown. Here, we investigated the spatiotemporal expression of Mdm2 by immunostaining and found that Mdm2 was highly expressed in the odontoblasts and slightly in the dental papilla cells of mouse incisors and molars. Gene knockdown and overexpression experiments verified that Mdm2 promoted the odontoblast-like differentiation of mouse dental papilla cells (mDPCs). Intranuclear colocalization and physical interaction between Mdm2 and distal-less 3 (Dlx3), a transcription factor important for odontoblast differentiation, was found during the odontoblast-like differentiation of mDPCs by double immunofluorescence and immunoprecipitation. Mdm2 was proved to monoubiquitinate Dlx3, which enhanced the expression of Dlx3 target gene Dspp. In addition, p53, the canonical substrate of Mdm2, was validated to be also ubiquitinated but degraded by Mdm2 during the odontoblast-like differentiation of mDPCs. Gene knockdown experiments confirmed that p53 inhibited the odontoblast-like differentiation of mDPCs. p53 and Mdm2 double knockdown partially rescued the reduced odontoblast-like differentiation by knockdown of Mdm2 alone. Taken together, our study revealed that Mdm2 promoted the odontoblast-like differentiation of mDPCs by ubiquitinating both Dlx3 and p53. On one hand, the monoubiquitination of Dlx3 by Mdm2 led to upregulation of Dspp, which is a marker of the odontoblast differentiation. On the other hand, ubiquitination of p53 by Mdm2 resulted in its degradation, which eliminated the inhibitory effect of p53 on the odontoblast-like differentiation of mDPCs.
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Affiliation(s)
- H Zheng
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - G Yang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - J Fu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Z Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - G Yuan
- The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Pediatric Dentistry, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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26
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Liu W, Li Y, Luo B. Current perspective on the regulation of FOXO4 and its role in disease progression. Cell Mol Life Sci 2020; 77:651-663. [PMID: 31529218 PMCID: PMC11104957 DOI: 10.1007/s00018-019-03297-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/21/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022]
Abstract
Forkhead box O4 (FOXO4) is a member of the FOXO family that regulates a number of genes involved in metabolism, cell cycle, apoptosis, and cellular homeostasis via transcriptional activity. It also mediates cell responses to oxidative stress and treatment with antitumor agents. The expression of FOXO4 is repressed by microRNAs in multiple cancer cells, while FOXO4 function is regulated by post-translational modifications and interaction with other proteins. The deregulation of FOXO4 is closely linked to the progression of several types of cancer, senescence, and other diseases. In this review, we present recent findings on the regulation of FOXO4 in physiological and pathological conditions and provide an overview of the complex role of FOXO4 in disease development and response to therapy.
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Affiliation(s)
- Wen Liu
- Department of Pathogenic Biology, Faculty of Medicine, Qingdao University, Qingdao, China
| | - Yong Li
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Faculty of Medicine, Qingdao University, Qingdao, China
| | - Bing Luo
- Department of Pathogenic Biology, Faculty of Medicine, Qingdao University, Qingdao, China.
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27
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Zhang W, Zhang J, Xu C, Zhang S, Bian S, Jiang F, Ni W, Qu L, Lu C, Ni R, Fan Y, Xiao M, Liu J. Ubiquitin-specific protease 7 is a drug-able target that promotes hepatocellular carcinoma and chemoresistance. Cancer Cell Int 2020; 20:28. [PMID: 32002017 PMCID: PMC6986148 DOI: 10.1186/s12935-020-1109-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 01/16/2020] [Indexed: 12/18/2022] Open
Abstract
Background Ubiquitin-specific protease 7 (USP7) is a de-ubiquitin enzyme that plays an essential role in multiple cancers and becomes a target for treatment. However, the role of USP7 and its therapeutic value for HCC remains unclear. Methods USP7 expression was examined in HCC tissues by western blot and immunohistochemistry. The correlation of USP7 and HCC prognosis was analyzed by Kaplan–Meier survival method. Mass spectrometry was determined and cell proliferation and tumorigenicity assays were conducted in vitro and in vivo treated by P22077 and sgRNA-USP7. Results USP7 expression was significantly increased in HCC and associated with its progression. Interestingly, many HCC cells are sensitive to USP7 inhibition by using P22077. P22077 treatment not only induced cell death but also inhibited cell proliferation and migration in Huh7 and SK-Hep1 cells. In a xenograft model, P22077 efficiently inhibited tumor growth. In chemo-resistant HCC cells, P22077 decreased cell sensitivity to chemotherapy. In addition, mass spectrometry reveals 224 of significantly changed proteins upon P22077 treatment. Conclusions We demonstrate a critical role of USP7 in HCC devolvement and chemoresistance. Disruption of USP7 function results in dis-regulated several key biological processes and subsequently activates BAX. USP7 might be a novel and drug-able target in HCC.
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Affiliation(s)
- Wei Zhang
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,2Medical College, Nantong University, Nantong, 226001 China
| | - Jingxin Zhang
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,2Medical College, Nantong University, Nantong, 226001 China
| | - Chenzhou Xu
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,2Medical College, Nantong University, Nantong, 226001 China
| | - Shiqing Zhang
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,2Medical College, Nantong University, Nantong, 226001 China
| | - Saiyan Bian
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,2Medical College, Nantong University, Nantong, 226001 China
| | - Feng Jiang
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Wenkai Ni
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Lishuai Qu
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Cuihua Lu
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Runzhou Ni
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Yihui Fan
- 3Laboratory of Medical Science, School of Medicine, Nantong University, Jiangsu, 226001 China
| | - Mingbing Xiao
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China.,4Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
| | - Jinxia Liu
- 1Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, 226001 Jiangsu People's Republic of China
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28
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Lam B, Roudier E. Considering the Role of Murine Double Minute 2 in the Cardiovascular System? Front Cell Dev Biol 2020; 7:320. [PMID: 31921839 PMCID: PMC6916148 DOI: 10.3389/fcell.2019.00320] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/21/2019] [Indexed: 01/26/2023] Open
Abstract
The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.
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Affiliation(s)
- Brian Lam
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
| | - Emilie Roudier
- Angiogenesis Research Group, School of Kinesiology and Health Sciences, Muscle Health Research Center, Faculty of Health, York University, Toronto, ON, Canada
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29
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García‐Cano J, Sánchez‐Tena S, Sala‐Gaston J, Figueras A, Viñals F, Bartrons R, Ventura F, Rosa JL. Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2. Mol Oncol 2020; 14:69-86. [PMID: 31665549 PMCID: PMC6944118 DOI: 10.1002/1878-0261.12592] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 09/30/2019] [Accepted: 10/28/2019] [Indexed: 12/20/2022] Open
Abstract
The p53 tumor suppressor protein is a transcription factor that plays a prominent role in protecting cells from malignant transformation. Protein levels of p53 and its transcriptional activity are tightly regulated by the ubiquitin E3 ligase MDM2, the gene expression of which is transcriptionally regulated by p53 in a negative feedback loop. The p53 protein is transcriptionally active as a tetramer, and this oligomerization state is modulated by a complex formed by NEURL4 and the ubiquitin E3 ligase HERC2. Here, we report that MDM2 forms a complex with oligomeric p53, HERC2, and NEURL4. HERC2 knockdown results in a decline in MDM2 protein levels without affecting its protein stability, as it reduces its mRNA expression by inhibition of its promoter activation. DNA damage induced by bleomycin dissociates MDM2 from the p53/HERC2/NEURL4 complex and increases the phosphorylation and acetylation of oligomeric p53 bound to HERC2 and NEURL4. Moreover, the MDM2 promoter, which contains p53-response elements, competes with HERC2 for binding of oligomeric, phosphorylated and acetylated p53. We integrate these findings in a model showing the pivotal role of HERC2 in p53-MDM2 loop regulation. Altogether, these new insights in p53 pathway regulation are of great interest in cancer and may provide new therapeutic targets.
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Affiliation(s)
- Jesús García‐Cano
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Susana Sánchez‐Tena
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Joan Sala‐Gaston
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Agnès Figueras
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Francesc Viñals
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Ramon Bartrons
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Francesc Ventura
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
| | - Jose Luis Rosa
- Departament de Ciències FisiològiquesInstitut d’Investigació de Bellvitge (IDIBELL)Universitat de Barcelona: Pavelló de GovernSpain
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30
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Choi YM, An S, Bae S, Jung JH. Mdm2 is required for HDAC3 monoubiquitination and stability. Biochem Biophys Res Commun 2019; 517:353-358. [PMID: 31358320 DOI: 10.1016/j.bbrc.2019.07.052] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 07/17/2019] [Indexed: 01/01/2023]
Abstract
HDAC3, one of the class I histone deacetylase modulates epigenetic landscape through histone modification. HDAC3 also interacts with non-histone proteins including p53 for deacetylation. Moreover, HDAC3 serves as a transcriptional repressor, interacting with NCor1/SMRT complex. Although HDAC3 plays a critical role for cellular homeostasis, regulatory mechanism of HDAC3 have been poorly understood. Here we report a novel regulatory mechanism of HDAC3 about its monoubiquitination and stabilization by Mdm2. HDAC3 levels were increased by ectopic expression of Mdm2 and decreased by Mdm2 ablation in various cell lines. We found that Mdm2 directly interacts with HDAC3 and induces HDAC3 protein levels without alteration of mRNA levels. Ectopic expression of wild type but not RING mutant of Mdm2 increased HDAC3 monoubiquitination. In addition, MdmX is beneficial for mdm2-mediated HDAC3 regulation. Ablation of Mdm2 and Mdm2/MdmX decreased cell migration along with the decrease of HDAC3 levels. These data provide an evidence that Mdm2 positively regulates HDAC3 monoubiquitination and stability.
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Affiliation(s)
- Yeong Min Choi
- GeneCellPharm Corporation, 375 Munjeong 2(i)-dong, Songpa-gu Seoul, 05836, Republic of Korea
| | - Sungkwan An
- Research Institute for Molecular-Targeted Drugs, Department of Cosmetics Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Seunghee Bae
- Research Institute for Molecular-Targeted Drugs, Department of Cosmetics Engineering, Konkuk University, Seoul, 05029, Republic of Korea
| | - Jin Hyuk Jung
- GeneCellPharm Corporation, 375 Munjeong 2(i)-dong, Songpa-gu Seoul, 05836, Republic of Korea.
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31
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Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view. Prog Neurobiol 2019; 181:101645. [PMID: 31229499 DOI: 10.1016/j.pneurobio.2019.101645] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 06/03/2019] [Accepted: 06/18/2019] [Indexed: 12/11/2022]
Abstract
Neurodegenerative diseases (NDDs), which are among the most important aging-related diseases, are typically characterized by neuronal damage and a progressive impairment in neurological function during aging. Few effective therapeutic targets for NDDs have been revealed; thus, an understanding of the pathogenesis of NDDs is important. Forkhead box O (FoxO) transcription factors have been implicated in the mechanisms regulating aging and longevity. The functions of FoxOs are regulated by diverse post-translational modifications (e.g., phosphorylation, acetylation, ubiquitination, methylation and glycosylation). FoxOs exert both detrimental and protective effects on NDDs. Therefore, an understanding of the precise function of FoxOs in NDDs will be helpful for developing appropriate treatment strategies. In this review, we first introduce the post-translational modifications of FoxOs. Next, the regulation of FoxO expression and post-translational modifications in the central nervous system (CNS) is described. Afterwards, we analyze and address the important roles of FoxOs in NDDs. Finally, novel potential directions of future FoxO research in NDDs are discussed. This review recapitulates essential facts and questions about the promise of FoxOs in treating NDDs, and it will likely be important for the design of further basic studies and to realize the potential for FoxOs as therapeutic targets in NDDs.
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32
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Wang Z, Kang W, You Y, Pang J, Ren H, Suo Z, Liu H, Zheng Y. USP7: Novel Drug Target in Cancer Therapy. Front Pharmacol 2019; 10:427. [PMID: 31114498 PMCID: PMC6502913 DOI: 10.3389/fphar.2019.00427] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 04/04/2019] [Indexed: 12/22/2022] Open
Abstract
Ubiquitin specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUB) that erases ubiquitin and protects substrate protein from degradation. Full activity of USP7 requires the C-terminal Ub-like domains fold back onto the catalytic domain, allowing the remodeling of the active site to a catalytically competent state by the C-terminal peptide. Until now, numerous proteins have been identified as substrates of USP7, which play a key role in cell cycle, DNA repair, chromatin remodeling, and epigenetic regulation. Aberrant activation or overexpression of USP7 may promote oncogenesis and viral disease, making it a target for therapeutic intervention. Currently, several synthetic small molecules have been identified as inhibitors of USP7, and applied in the treatment of diverse diseases. Hence, USP7 may be a promising therapeutic target for the treatment of cancer.
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Affiliation(s)
- Zhiru Wang
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China.,Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Wenting Kang
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
| | - Yinghua You
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
| | - Jingru Pang
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
| | - Hongmei Ren
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
| | - Zhenhe Suo
- Pathology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Hongmin Liu
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
| | - Yichao Zheng
- School of Pharmaceutical Sciences, Zhenghzou University, Zhengzhou, China.,Collaborative Innovation Centre of New Drug Research and Safety Evaluation, Henan Province, and Key Laboratory of Advanced Drug Preparation Technologies, Zhengzhou University, and Key Laboratory of Henan Province for Drug Quality and Evaluation, Ministry of Education of China, Zhengzhou, China
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MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene 2018; 38:2501-2515. [PMID: 30532073 DOI: 10.1038/s41388-018-0605-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/27/2018] [Accepted: 11/13/2018] [Indexed: 01/12/2023]
Abstract
MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.
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Ubiquitination and SUMOylation in the chronic inflammatory tumor microenvironment. Biochim Biophys Acta Rev Cancer 2018; 1870:165-175. [DOI: 10.1016/j.bbcan.2018.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 08/10/2018] [Accepted: 08/15/2018] [Indexed: 12/28/2022]
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35
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Liu J, Zou X, Gotoh T, Brown AM, Jiang L, Wisdom EL, Kim JK, Finkielstein CV. Distinct control of PERIOD2 degradation and circadian rhythms by the oncoprotein and ubiquitin ligase MDM2. Sci Signal 2018; 11:11/556/eaau0715. [PMID: 30425162 DOI: 10.1126/scisignal.aau0715] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The circadian clock relies on posttranslational modifications to set the timing for degradation of core regulatory components, which drives clock progression. Ubiquitin-modifying enzymes that target clock components for degradation mainly recognize phosphorylated substrates. Degradation of the circadian clock component PERIOD 2 (PER2) is mediated by its phospho-specific recognition by β-transducin repeat-containing proteins (β-TrCPs), which are F-box-containing proteins that function as substrate recognition subunits of the SCFβ-TRCP ubiquitin ligase complex. However, this mode of regulating PER2 stability falls short of explaining the persistent oscillatory phenotypes reported in biological systems lacking functional elements of the phospho-dependent PER2 degradation machinery. We identified PER2 as a previously uncharacterized substrate for the ubiquitin ligase mouse double minute 2 homolog (MDM2) and found that MDM2 targeted PER2 for degradation in a manner independent of PER2 phosphorylation. Deregulation of MDM2 plays a major role in oncogenesis by contributing to the accumulation of genomic and epigenomic alterations that favor tumor development. MDM2-mediated PER2 turnover was important for defining the circadian period length in mammalian cells, a finding that emphasizes the connection between the circadian clock and cancer. Our results not only broaden the range of specific substrates of MDM2 beyond the cell cycle to include circadian components but also identify a previously unknown regulator of the clock as a druggable node that is often found to be deregulated during tumorigenesis.
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Affiliation(s)
- JingJing Liu
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA
| | - Xianlin Zou
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA
| | - Tetsuya Gotoh
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA
| | - Anne M Brown
- Research and Informatics, University Libraries, Virginia Tech, Blacksburg, VA, USA
| | - Liang Jiang
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA
| | - Esther L Wisdom
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA
| | - Jae Kyoung Kim
- Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Carla V Finkielstein
- Integrated Cellular Responses Laboratory, Department of Biological Sciences, Biocomplexity Institute, Virginia Tech, Blacksburg, VA, USA.
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36
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Qin JJ, Li X, Hunt C, Wang W, Wang H, Zhang R. Natural products targeting the p53-MDM2 pathway and mutant p53: Recent advances and implications in cancer medicine. Genes Dis 2018; 5:204-219. [PMID: 30320185 PMCID: PMC6176154 DOI: 10.1016/j.gendis.2018.07.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 07/17/2018] [Indexed: 12/13/2022] Open
Abstract
The p53 tumor suppressor plays a major role in controlling the initiation and development of cancer by regulating cell cycle arrest, apoptosis, senescence, and DNA repair. The MDM2 oncogene is a major negative regulator of p53 that inhibits the activity of p53 and reduces its protein stability. MDM2, p53, and the p53-MDM2 pathway represent well-documented targets for preventing and/or treating cancer. Natural products, especially those from medicinal and food plants, are a rich source for the discovery and development of novel therapeutic and preventive agents against human cancers. Many natural product-derived MDM2 inhibitors have shown potent efficacy against various human cancers. In contrast to synthetic small-molecule MDM2 inhibitors, the majority of which have been designed to inhibit MDM2-p53 binding and activate p53, many natural product inhibitors directly decrease MDM2 expression and/or MDM2 stability, exerting their anticancer activity in both p53-dependent and p53-independent manners. More recently, several natural products have been reported to target mutant p53 in cancer. Therefore, identification of natural products targeting MDM2, mutant p53, and the p53-MDM2 pathway can provide a promising strategy for the development of novel cancer chemopreventive and chemotherapeutic agents. In this review, we focus our discussion on the recent advances in the discovery and development of anticancer natural products that target the p53-MDM2 pathway, emphasizing several emerging issues, such as the efficacy, mechanism of action, and specificity of these natural products.
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Affiliation(s)
- Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA
| | - Xin Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA
| | - Courtney Hunt
- Center for Drug Discovery, University of Houston, Houston, TX, 77204, USA
| | - Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA
- Center for Drug Discovery, University of Houston, Houston, TX, 77204, USA
| | - Hui Wang
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA
- Center for Drug Discovery, University of Houston, Houston, TX, 77204, USA
- Corresponding author. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX, 77204, USA. Fax: +1 713 743 1229.
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Jiang S, Yang Z, Di S, Hu W, Ma Z, Chen F, Yang Y. Novel role of forkhead box O 4 transcription factor in cancer: Bringing out the good or the bad. Semin Cancer Biol 2018; 50:1-12. [DOI: 10.1016/j.semcancer.2018.04.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 04/28/2018] [Indexed: 10/17/2022]
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Bourgeois B, Madl T. Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Lett 2018; 592:2083-2097. [PMID: 29683489 PMCID: PMC6033032 DOI: 10.1002/1873-3468.13057] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 02/06/2023]
Abstract
Forkhead box O (FOXO) and p53 proteins are transcription factors that regulate diverse signalling pathways to control cell cycle, apoptosis and metabolism. In the last decade both FOXO and p53 have been identified as key players in aging, and their misregulation is linked to numerous diseases including cancers. However, many of the underlying molecular mechanisms remain mysterious, including regulation of ageing by FOXOs and p53. Several activities appear to be shared between FOXOs and p53, including their central role in the regulation of cellular senescence. In this review, we will focus on the recent advances on the link between FOXOs and p53, with a particular focus on the FOXO4‐p53 axis and the role of FOXO4/p53 in cellular senescence. Moreover, we discuss potential strategies for targeting the FOXO4‐p53 interaction to modulate cellular senescence as a drug target in treatment of aging‐related diseases and morbidity.
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Affiliation(s)
- Benjamin Bourgeois
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria
| | - Tobias Madl
- Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Austria.,BioTechMed, Graz, Austria
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39
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Balaji V, Pokrzywa W, Hoppe T. Ubiquitylation Pathways In Insulin Signaling and Organismal Homeostasis. Bioessays 2018; 40:e1700223. [PMID: 29611634 DOI: 10.1002/bies.201700223] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/26/2018] [Indexed: 12/26/2022]
Abstract
The insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine-tuned cascade of signaling events induced by insulin/IGF-1, which is precisely controlled by post-translational modifications. The ubiquitin/proteasome-system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF-1 receptor, the stability of downstream insulin/IGF-1 signaling targets, and activity of nuclear receptors for control of gene expression. An age-related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis.
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Affiliation(s)
- Vishnu Balaji
- Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany
| | - Wojciech Pokrzywa
- Laboratory of Protein Metabolism in Development and Aging, International Institute of Molecular and Cell Biology, Warsaw, Poland
| | - Thorsten Hoppe
- Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany
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40
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Ma Z, Xin Z, Hu W, Jiang S, Yang Z, Yan X, Li X, Yang Y, Chen F. Forkhead box O proteins: Crucial regulators of cancer EMT. Semin Cancer Biol 2018; 50:21-31. [PMID: 29427645 DOI: 10.1016/j.semcancer.2018.02.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 12/02/2017] [Accepted: 02/05/2018] [Indexed: 12/12/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets.
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Affiliation(s)
- Zhiqiang Ma
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China; Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Zhenlong Xin
- Department of Occupational and Environmental Health and The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Wei Hu
- Department of Immunology, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
| | - Fulin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China.
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41
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Role of Forkhead Box O (FOXO) transcription factor in aging and diseases. Gene 2018; 648:97-105. [PMID: 29428128 DOI: 10.1016/j.gene.2018.01.051] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/26/2017] [Accepted: 01/14/2018] [Indexed: 12/21/2022]
Abstract
Fork head box O (FOXO) transcription factor is a key player in an evolutionarily conserved pathway. The mammalian FOXO family consists of FOXO1, 3, 4 and 6, are highly similar in their structure, function and regulation. To maintain optimum body function, the organisms have developed complex mechanisms for homeostasis. Importantly, it is well known that when these mechanisms dysregulate it results in the development of age-related disease. FOXO proteins are involved in a diverse cellular function and also have clinical significance including cell cycle arrest, cell differentiation, tumour suppression, DNA repair, longevity, diabetic complications, immunity, wound healing, regulation of metabolism and thus treatment of several types of diseases. By the combinations of post-translational modifications FOXO's serve as a 'molecular code' to sense external stimuli and recruit it as to specific regions of the genome and provide an integrated cellular response to changing physiological conditions. Akt/Protein kinase B a signaling pathway as a main regulator of FOXO to perform a diverse function in organisms. The present review summarizes the molecular and clinical aspects of FOXO transcription factor. And also elaborate the interaction of FOXO with the nucleosome remodelling complex to target genes, which is essential to cellular homeostasis.
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Hou T, Li Z, Zhao Y, Zhu WG. Mechanisms controlling the anti-neoplastic functions of FoxO proteins. Semin Cancer Biol 2017; 50:101-114. [PMID: 29155239 DOI: 10.1016/j.semcancer.2017.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 10/18/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023]
Abstract
The Forkhead box O (FoxO) proteins comprise a family of evolutionarily conserved transcription factors that predominantly function as tumor suppressors. These proteins assume diverse roles in the cellular anti-neoplastic response, including regulation of apoptosis and autophagy, cancer metabolism, cell-cycle arrest, oxidative stress and the DNA damage response. More recently, FoxO proteins have been implicated in cancer immunity and cancer stem-cell (CSC) homeostasis. Interestingly, in some sporadic sub-populations, FoxO protein function may also be manipulated by factors such as β-catenin whereby they instead can facilitate cancer progression via maintenance of CSC properties or promoting drug resistance or metastasis and invasion. This review highlights the essential biological functions of FoxOs and explores the areas that may be exploited in FoxO protein signaling pathways in the development of novel cancer therapeutic agents.
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Affiliation(s)
- Tianyun Hou
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Zhiming Li
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Ying Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Wei-Guo Zhu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
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Abstract
Forkhead box O (FOXO) transcription factors are central regulators of cellular homeostasis. FOXOs respond to a wide range of external stimuli, including growth factor signaling, oxidative stress, genotoxic stress, and nutrient deprivation. These signaling inputs regulate FOXOs through a number of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and methylation. Covalent modifications can affect localization, DNA binding, and interactions with other cofactors in the cell. FOXOs integrate the various modifications to regulate cell type-specific gene expression programs that are essential for metabolic homeostasis, redox balance, and the stress response. Together, these functions are critical for coordinating a response to environmental fluctuations in order to maintain cellular homeostasis during development and to support healthy aging.
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Regulatory effects of antitumor agent matrine on FOXO and PI3K-AKT pathway in castration-resistant prostate cancer cells. SCIENCE CHINA-LIFE SCIENCES 2017; 61:550-558. [PMID: 29119376 DOI: 10.1007/s11427-016-9050-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 08/28/2017] [Indexed: 01/09/2023]
Abstract
We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly defined. In this study, using various techniques such as high throughput sequencing technology, bioinformatics, quantitative real-time PCR, and immunoblot analysis, we aimed to understand whether matrine serves as a novel regulator of FOXO and PI3K-AKT signaling pathway. DU145 and PC-3 cell lines were cultured for 24 h in vitro. Cells were treated with either matrine or control serum for 48 h, followed by extraction of total RNA. The RNA was sequenced using HiSeq 2500 high-throughput sequencing platform (Illumina). A gene library was established and quality analysis of read data carried out. Integrated database from the website DAVID was used to analyze Gene Ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway of differential genes was used for pathway analysis, screening for fold differences of more than two times. The FOXO and PI3K-AKT signaling pathways were screened, and expression levels of mRNA and core protein detected by real-time PCR and immunoblotting, respectively. High throughput sequencing and GO analysis revealed that differentially expressed genes before and after treatment played an important role in cell metabolic process, growth process, anatomical structure formation, cellular component organization, and biological regulation. KEGG signal pathway analysis revealed that FOXO and PI3K-AKT signal pathways had a significant difference between before and after matrine-treated androgen-independent prostate cancer cells PC-3 and DU145. Real-time PCR showed that matrine treatment led to a significant increase in the expression levels of FOXO1A, FOXO3A, FOXO4, and FOXO6 in DU145 and PC-3 cells (P<0.01 or P<0.05), whereas the PI3K expression levels decreased (P<0.01). Similarly, immunoblotting revealed a significant increase (P<0.05) in the expression levels of FOXO1A FOXO3A, FOXO4, and FOXO6 in both PC-3 and DU145 cells, whereas PI3K expression levels decreased (P<0.05). Matrine had a broad regulating effect on the mRNA expression profiles of both PC-3 and DU145 cells. Matrine may inhibit cell proliferation, migration, as well as invasion, and induce apoptosis in both PC-3 and DU145 cells through FOXO and PI3K-AKT signaling pathways. Matrine could therefore be used as a complementary drug to present chemotherapeutic agents, for treating androgen-independent prostate cancer.
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45
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Wang D, Ma L, Wang B, Liu J, Wei W. E3 ubiquitin ligases in cancer and implications for therapies. Cancer Metastasis Rev 2017; 36:683-702. [DOI: 10.1007/s10555-017-9703-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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46
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Zhang F, Virshup DM, Cheong JK. Oncogenic RAS-induced CK1α drives nuclear FOXO proteolysis. Oncogene 2017; 37:363-376. [PMID: 28945225 PMCID: PMC5799771 DOI: 10.1038/onc.2017.334] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 07/30/2017] [Accepted: 08/12/2017] [Indexed: 12/18/2022]
Abstract
Evasion of forkhead box O (FOXO) family of longevity-related transcription factors-mediated growth suppression is necessary to promote cancer development. Since somatic alterations or mutations and transcriptional dysregulation of the FOXO genes are infrequent in human cancers, it remains unclear how these tumour suppressors are eliminated from cancer cells. The protein stability of FOXO3A is regulated by Casein Kinase 1 alpha (CK1α) in an oncogenic RAS-specific manner, but whether this mode of regulation extends to related FOXO family members is unknown. Here we report that CK1α similarly destabilizes FOXO4 in RAS-mutant cells by phosphorylation at serines 265/268. The CK1α-dependent phosphoregulation of FOXO4 is primed, in part, by the PI3K/AKT effector axis of oncogenic RAS signalling. In addition, mutant RAS coordinately elevates proteasome subunit expression and proteolytic activity to eradicate nuclear FOXO4 proteins from RAS-mutant cancer cells. Importantly, dual inhibition of CK1α and the proteasome synergistically inhibited the growth of multiple RAS-mutant human cancer cell lines of diverse tissue origin by blockade of nuclear FOXO4 degradation and induction of caspase-dependent apoptosis. Our findings challenge the current paradigm that nuclear export regulates the proteolysis of FOXO3A/4 tumour suppressors in the context of cancer and illustrates how oncogenic RAS-mediated degradation of FOXOs, via post-translational mechanisms, blocks these important tumour suppressors.
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Affiliation(s)
- F Zhang
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
| | - D M Virshup
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.,Department of Biochemistry, National University of Singapore, Singapore.,Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - J K Cheong
- Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore
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47
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Qin JJ, Wang W, Zhang R. Experimental Therapy of Advanced Breast Cancer: Targeting NFAT1-MDM2-p53 Pathway. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2017; 151:195-216. [PMID: 29096894 PMCID: PMC6663080 DOI: 10.1016/bs.pmbts.2017.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Advanced breast cancer, especially advanced triple-negative breast cancer, is typically more aggressive and more difficult to treat than other breast cancer phenotypes. There is currently no curable option for breast cancer patients with advanced diseases, highlighting the urgent need for novel treatment strategies. We have recently discovered that the nuclear factor of activated T cells 1 (NFAT1) activates the murine double minute 2 (MDM2) oncogene. Both MDM2 and NFAT1 are overexpressed and constitutively activated in breast cancer, particularly in advanced breast cancer, and contribute to its initiation, progression, and metastasis. MDM2 regulates cancer cell proliferation, cell cycle progression, apoptosis, migration, and invasion through both p53-dependent and -independent mechanisms. We have proposed to target the NFAT1-MDM2-p53 pathway for the treatment of human cancers, especially breast cancer. We have recently identified NFAT1 and MDM2 dual inhibitors that have shown excellent in vitro and in vivo activities against breast cancer, including triple-negative breast cancer. Herein, we summarize recent advances made in the understanding of the oncogenic functions of MDM2 and NFAT1 in breast cancer, as well as current targeting strategies and representative inhibitors. We also propose several strategies for inhibiting the NFAT1-MDM2-p53 pathway, which could be useful for developing more specific and effective inhibitors for breast cancer therapy.
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Affiliation(s)
- Jiang-Jiang Qin
- University of Houston, Houston, TX, United States; Texas Tech University Health Sciences Center, Amarillo, TX, United States
| | - Wei Wang
- University of Houston, Houston, TX, United States; Texas Tech University Health Sciences Center, Amarillo, TX, United States
| | - Ruiwen Zhang
- University of Houston, Houston, TX, United States; Texas Tech University Health Sciences Center, Amarillo, TX, United States.
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Correlations of Foxo3 and Foxo4 expressions with clinicopathological features and prognosis of bladder cancer. Pathol Res Pract 2017; 213:766-772. [PMID: 28554751 DOI: 10.1016/j.prp.2017.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 03/13/2017] [Accepted: 04/12/2017] [Indexed: 11/21/2022]
Abstract
OBJECTIVE The study is performed to explore the correlations of forkhead box O3 (FoxO3) and forkhead box O4 (FoxO4) expressions with clinicopathological features and prognosis of bladder cancer. METHODS Bladder cancer tissues and adjacent normal tissues from the recruited 222 patients were collected. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry were applied to determine the expressions of FoxO3 and FoxO4. Spearman correlation analysis was conducted to examine the correlation between the expressions of FoxO3 and FoxO4. All patients were followed up and overall survival (OS) and disease-free survival (DFS) were recorded. Kaplan-Meier survival curve was drawn to determine the associations of FoxO3 and FoxO4 expressions and postoperative survival. Cox proportional hazards model was conducted to analyze the risk factors for poor prognosis of bladder cancer. RESULTS The mRNA and expressions of FoxO3 and FoxO4 proteins in the bladder cancer tissues were lower than that in the adjacent normal tissues (both P<0.05). The positive rates of FoxO3 and FoxO4 were lower in the patients with lymph node metastasis than that in the patients without lymph node metastasis (P<0.05), and significantly lower in the patients with non-muscle invasive bladder cancer (Tis-T1) than in those with non-muscle invasive bladder cancer (T2-T3) in TNM staging, and remarkably lower in the patients with high grade than in those with low grade in the histological type (P<0.05). Furthermore, the expressions of FoxO3 and FoxO4 were positively correlated in the bladder cancer tissues (P<0.05). Negative expressions of FoxO3 and FoxO4 and lymph node metastasis were the risk factors for the poor prognosis of bladder cancer. CONCLUSIONS The FoxO3 and FoxO4 expressions may potentially associate with the clinicopathological features and prognosis of bladder cancer.
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Wang L, Zhu B, Wang S, Wu Y, Zhan W, Xie S, Shi H, Yu R. Regulation of glioma migration and invasion via modification of Rap2a activity by the ubiquitin ligase Nedd4-1. Oncol Rep 2017; 37:2565-2574. [PMID: 28405688 PMCID: PMC5428538 DOI: 10.3892/or.2017.5572] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 10/18/2016] [Indexed: 12/26/2022] Open
Abstract
Νeuronal precursor cell expressed and developmentally downregulated protein (Nedd4-1) is an E3 ubiquitin ligase with critical roles in the pathogenesis of cancer. Herein, we demonstrated that Nedd4-1 protein was upregulated in glioma tissues vs. that in non-cancerous tissues by western blotting and immunohistochemistry. Scratch migration and Transwell chamber assays indicated that downregulation of Nedd4-1 significantly reduced the migration and invasion of the glioma cell lines U251 and U87. Conversely, overexpression of Nedd4-1 obviously enhanced the migratory and invasive capacities in both cell lines. To investigate the role of Nedd4-1 and the intracellular pathways involved, we performed pull-down and co-immunoprecipitation assays, and recognized that Nedd4-1, TNIK and Rap2a formed a complex. Moreover, Nedd4-1 selectively ubiquitinated its specific substrates, the wild-type Rap2a (WT-Rap2a) and dominant-active Rap2a (DA-Rap2a) rather than the dominant-negative Rap2a (DN-Rap2a) in the U251 cells. Subsequently, we demonstrated that Rap2a was robustly ubiquitinated by Nedd4-1 along with the K63-linked, but not the K48-linked ubiquitin chain, which significantly inhibited GTP-Rap2a activity by GST-RalGDS pull-down assay. To further verify whether the ubiquitination of Rap2a by Nedd4-1 regulated the migration and invasion of glioma cells, Nedd4-1, HA-tagged ubiquitin and its mutants as well as WT-Rap2a were co-transfected in the U251 and U87 cell lines. The results confirmed that Nedd4-1 inhibited GTP-Rap2a activity, and promoted the migration and invasion of glioma cells. In brief, our findings demonstrated the important role of Nedd4-1 in regulating the migration and invasion of glioma cells via the Nedd4-1/Rap2a pathway, which may qualify Nedd4-1 as a viable therapeutic target for glioma.
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Affiliation(s)
- Lei Wang
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Bingxin Zhu
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Shiquan Wang
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Yuxuan Wu
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Wenjian Zhan
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Shao Xie
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Hengliang Shi
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
| | - Rutong Yu
- Insitute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China
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Liu X, Cai X, Hu B, Mei Z, Zhang D, Ouyang G, Wang J, Zhang W, Xiao W. Forkhead Transcription Factor 3a (FOXO3a) Modulates Hypoxia Signaling via Up-regulation of the von Hippel-Lindau Gene (VHL). J Biol Chem 2016; 291:25692-25705. [PMID: 27777301 DOI: 10.1074/jbc.m116.745471] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 10/20/2016] [Indexed: 01/26/2023] Open
Abstract
FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor α degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown. Here we show that FOXO3a directly binds to the VHL promoter and up-regulates VHL expression. Using a zebrafish model, we confirmed the up-regulation of vhl by foxo3b, an ortholog of mammalian FOXO3a Furthermore, by employing the clustered regularly interspaced short palindromic repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (CRISPR/Cas9) technology, we deleted foxo3b in zebrafish and determined that expression of hypoxia-inducible genes was affected under hypoxia. Moreover, foxo3b-null zebrafish exhibited impaired acute hypoxic tolerance, resulting in death. In conclusion, our findings suggest that, by modulating hypoxia-inducible factor activity via up-regulation of VHL, FOXO3a (foxo3b) plays an important role in survival in response to hypoxic stress.
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Affiliation(s)
- Xing Liu
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Xiaolian Cai
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Bo Hu
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Zhichao Mei
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Dawei Zhang
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Gang Ouyang
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Jing Wang
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Wei Zhang
- From the Key Laboratory of Aquatic Biodiversity and Conservation and
| | - Wuhan Xiao
- From the Key Laboratory of Aquatic Biodiversity and Conservation and .,State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
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