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Choi S, Yu E, Park S, Oh SW, Kwon K, Kim G, Ha H, Shin HS, Min S, Song M, Cho JY, Lee J. Protective effect of melatonin against blue light-induced cell damage via the TRPV1-YAP pathway in cultured human epidermal keratinocytes. Biofactors 2025; 51:e70015. [PMID: 40183558 PMCID: PMC11970215 DOI: 10.1002/biof.70015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Accepted: 03/26/2025] [Indexed: 04/05/2025]
Abstract
Although blue light has been known to negatively affect skin cells, its detailed signaling mechanisms and anti-blue light agents have not been clearly elucidated. We investigated the involvement of Yes-associated protein (YAP)-mediated Hippo signaling in blue light-induced apoptosis, depending on the degree of blue light exposure. Additionally, we elucidated the effects of melatonin on blue light-irradiated keratinocytes and examined their action mechanisms. After blue light irradiation, its effects and antagonizing effects of melatonin on cell proliferation, apoptosis, DNA damage, and transient receptor potential vanilloid 1 (TRPV1)/YAP-mediated signaling were examined in HaCaT cells using western blots, image analysis, flow cytometric analysis, co-immunoprecipitation, and immunocytochemistry. We found that melatonin treatment attenuated the reduced cell viability and increased production of reactive oxygen species (ROS) in response to blue light irradiation. In the experiments to investigate the mechanism of action of blue light and melatonin, we found that YAP changed its binding protein, either p73 or TEAD, depending on the degree of blue light exposure. Melatonin treatment reduced blue light-induced phosphorylation of TRPV1 and MST1/2. Upon treatment with capsazepine, an antagonist of TRPV1, MST1/2 activation also reduced. Furthermore, we found that prolonged blue light irradiation induced DNA damage, which in turn induced YAP-p73 nuclear translocation. These effects were also notably attenuated by melatonin. These findings indicate that depending on the duration of blue light irradiation, two different YAP-mediated Hippo signaling pathways are activated. Additionally, these findings suggest that melatonin could be a potential therapeutic agent for blue light-induced skin damage.
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Affiliation(s)
- Seoyoung Choi
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Eunbi Yu
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - See‐Hyoung Park
- Department of Bio and Chemical EngineeringHongik UniversitySejong CityKorea
| | - Sae Woong Oh
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Kitae Kwon
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Gyeonghyeon Kim
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Heejun Ha
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Hee Seon Shin
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Seokhyeon Min
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Minkyung Song
- Integrative Research of T cells Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
- Department of Biopharmaceutical ConvergenceSungkyunkwan UniversitySuwon CityKorea
| | - Jae Youl Cho
- Molecular Immunology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
| | - Jongsung Lee
- Molecular Dermatology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon CityKorea
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2
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Slaninová V, Heron-Milhavet L, Robin M, Jeanson L, Aissanou A, Kantar D, Tosi D, Bréhélin L, Gongora C, Djiane A. The Hippo pathway terminal effector TAZ/WWTR1 mediates oxaliplatin sensitivity in p53 proficient colon cancer cells. BMC Cancer 2024; 24:587. [PMID: 38741073 PMCID: PMC11092100 DOI: 10.1186/s12885-024-12316-4] [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: 09/25/2023] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.
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Affiliation(s)
- Věra Slaninová
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | | | - Mathilde Robin
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- LIRMM, Univ Montpellier, Inserm, CNRS, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | - Laura Jeanson
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Adam Aissanou
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diala Kantar
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
| | - Diego Tosi
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France
- Fondazione Gianni Bonadonna, Milan, Italy
| | | | - Céline Gongora
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
| | - Alexandre Djiane
- IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France.
- IRCM, Univ Montpellier, Inserm, ICM, CNRS, Montpellier, France.
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3
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Jung O, Baek MJ, Wooldrik C, Johnson KR, Fisher KW, Lou J, Ricks TJ, Wen T, Best MD, Cryns VL, Anderson RA, Choi S. Nuclear phosphoinositide signaling promotes YAP/TAZ-TEAD transcriptional activity in breast cancer. EMBO J 2024; 43:1740-1769. [PMID: 38565949 PMCID: PMC11066040 DOI: 10.1038/s44318-024-00085-6] [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: 03/21/2023] [Revised: 02/29/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024] Open
Abstract
The Hippo pathway effectors Yes-associated protein 1 (YAP) and its homolog TAZ are transcriptional coactivators that control gene expression by binding to TEA domain (TEAD) family transcription factors. The YAP/TAZ-TEAD complex is a key regulator of cancer-specific transcriptional programs, which promote tumor progression in diverse types of cancer, including breast cancer. Despite intensive efforts, the YAP/TAZ-TEAD complex in cancer has remained largely undruggable due to an incomplete mechanistic understanding. Here, we report that nuclear phosphoinositides function as cofactors that mediate the binding of YAP/TAZ to TEADs. The enzymatic products of phosphoinositide kinases PIPKIα and IPMK, including phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-trisphosphate (P(I3,4,5)P3), bridge the binding of YAP/TAZ to TEAD. Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.
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Affiliation(s)
- Oisun Jung
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Min-Jeong Baek
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Interdisciplinary Graduate Program in Biomedical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Colin Wooldrik
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Interdisciplinary Graduate Program in Biomedical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Keith R Johnson
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Oral Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kurt W Fisher
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jinchao Lou
- Department of Chemistry, University of Tennessee, 1420 Circle Drive, Knoxville, TN, 37996, USA
| | - Tanei J Ricks
- Department of Chemistry, University of Memphis, 3744 Walker Avenue, Memphis, TN, 38152, USA
| | - Tianmu Wen
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael D Best
- Department of Chemistry, University of Tennessee, 1420 Circle Drive, Knoxville, TN, 37996, USA
| | - Vincent L Cryns
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Richard A Anderson
- University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Suyong Choi
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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Silonov SA, Mokin YI, Nedelyaev EM, Smirnov EY, Kuznetsova IM, Turoverov KK, Uversky VN, Fonin AV. On the Prevalence and Roles of Proteins Undergoing Liquid-Liquid Phase Separation in the Biogenesis of PML-Bodies. Biomolecules 2023; 13:1805. [PMID: 38136675 PMCID: PMC10741438 DOI: 10.3390/biom13121805] [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: 11/14/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
The formation and function of membrane-less organelles (MLOs) is one of the main driving forces in the molecular life of the cell. These processes are based on the separation of biopolymers into phases regulated by multiple specific and nonspecific inter- and intramolecular interactions. Among the realm of MLOs, a special place is taken by the promyelocytic leukemia nuclear bodies (PML-NBs or PML bodies), which are the intranuclear compartments involved in the regulation of cellular metabolism, transcription, the maintenance of genome stability, responses to viral infection, apoptosis, and tumor suppression. According to the accepted models, specific interactions, such as SUMO/SIM, the formation of disulfide bonds, etc., play a decisive role in the biogenesis of PML bodies. In this work, a number of bioinformatics approaches were used to study proteins found in the proteome of PML bodies for their tendency for spontaneous liquid-liquid phase separation (LLPS), which is usually caused by weak nonspecific interactions. A total of 205 proteins found in PML bodies have been identified. It has been suggested that UBC9, P53, HIPK2, and SUMO1 can be considered as the scaffold proteins of PML bodies. It was shown that more than half of the proteins in the analyzed proteome are capable of spontaneous LLPS, with 85% of the analyzed proteins being intrinsically disordered proteins (IDPs) and the remaining 15% being proteins with intrinsically disordered protein regions (IDPRs). About 44% of all proteins analyzed in this study contain SUMO binding sites and can potentially be SUMOylated. These data suggest that weak nonspecific interactions play a significantly larger role in the formation and biogenesis of PML bodies than previously expected.
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Affiliation(s)
- Sergey A. Silonov
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Yakov I. Mokin
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Eugene M. Nedelyaev
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Eugene Y. Smirnov
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Irina M. Kuznetsova
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Konstantin K. Turoverov
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA;
| | - Alexander V. Fonin
- Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (S.A.S.); (Y.I.M.); (E.M.N.); (E.Y.S.); (I.M.K.); (K.K.T.)
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5
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Tsitsou-Kampeli A, Suzzi S, Kenigsbuch M, Satomi A, Strobelt R, Singer O, Feldmesser E, Purnapatre M, Colaiuta SP, David E, Cahalon L, Hahn O, Wyss-Coray T, Shaul Y, Amit I, Schwartz M. Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis. Cell Rep Med 2023; 4:101278. [PMID: 37944529 PMCID: PMC10694665 DOI: 10.1016/j.xcrm.2023.101278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 05/26/2023] [Accepted: 10/11/2023] [Indexed: 11/12/2023]
Abstract
The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.
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Affiliation(s)
| | - Stefano Suzzi
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel.
| | - Mor Kenigsbuch
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Akisawa Satomi
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Romano Strobelt
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Oded Singer
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Ester Feldmesser
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | | | | | - Eyal David
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Liora Cahalon
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Oliver Hahn
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Tony Wyss-Coray
- Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Michal Schwartz
- Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel.
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Strobelt R, Adler J, Shaul Y. The Transmembrane Protease Serine 2 (TMPRSS2) Non-Protease Domains Regulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike-Mediated Virus Entry. Viruses 2023; 15:2124. [PMID: 37896901 PMCID: PMC10612036 DOI: 10.3390/v15102124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 10/13/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells by binding to the angiotensin-converting enzyme 2 (hACE2) receptor. This process is aided by the transmembrane protease serine 2 (TMPRSS2), which enhances entry efficiency and infectiousness by cleaving the SARS-CoV-2 surface glycoprotein (Spike). The cleavage primes the Spike protein, promoting membrane fusion instead of receptor-mediated endocytosis. Despite the pivotal role played by TMPRSS2, our understanding of its non-protease distinct domains remains limited. In this report, we present evidence indicating the potential phosphorylation of a minimum of six tyrosine residues within the cytosolic tail (CT) of TMPRSS2. Via the use of TMPRSS2 CT phospho-mimetic mutants, we observed a reduction in TMPRSS2 protease activity, accompanied by a decrease in SARS-CoV-2 pseudovirus transduction, which was found to occur mainly via the endosomal pathway. We expanded our investigation beyond TMPRSS2 CT and discovered the involvement of other non-protease domains in regulating infection. Our co-immunoprecipitation experiments demonstrated a strong interaction between TMPRSS2 and Spike. We revealed a 21 amino acid long TMPRSS2-Spike-binding region (TSBR) within the TMPRSS2 scavenger receptor cysteine-rich (SRCR) domain that contributes to this interaction. Our study sheds light on novel functionalities associated with TMPRSS2's cytosolic tail and SRCR region. Both of these regions have the capability to regulate SARS-CoV-2 entry pathways. These findings contribute to a deeper understanding of the complex interplay between viral entry and host factors, opening new avenues for potential therapeutic interventions.
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Affiliation(s)
| | | | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel
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7
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Steinberger S, Adler J, Shaul Y. Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity. Biomolecules 2023; 13:992. [PMID: 37371572 DOI: 10.3390/biom13060992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Proteasomes critically regulate proteostasis via protein degradation. Proteasomes are multi-subunit complexes composed of the 20S proteolytic core particle (20S CP) that, in association with one or two 19S regulatory particles (19S RPs), generates the 26S proteasome, which is the major proteasomal complex in cells. Native gel protocols are used to investigate the 26S/20S ratio. However, a simple method for detecting these proteasome complexes in cells is missing. To this end, using CRISPR technology, we YFP-tagged the endogenous PSMB6 (β1) gene, a 20S CP subunit, and co-tagged endogenous PSMD6 (Rpn7), a 19S RP subunit, with the mScarlet fluorescent protein. We observed the colocalization of the YFP and mScarlet fluorescent proteins in the cells, with higher nuclear accumulation. Nuclear proteasomal granules are formed under osmotic stress, and all were positive for YFP and mScarlet. Previously, we have reported that PSMD1 knockdown, one of the 19 RP subunits, gives rise to a high level of "free" 20S CPs. Intriguingly, under this condition, the 20S-YFP remained nuclear, whereas the PSMD6-mScarlet was mostly in cytoplasm, demonstrating the distinct subcellular distribution of uncapped 20S CPs. Lately, we have shown that the PSMA3 (α7) C-terminus, a 20S CP subunit, binds multiple intrinsically disordered proteins (IDPs). Remarkably, the truncation of the PSMA3 C-terminus is phenotypically reminiscent of PSMD1 knockdown. These data suggest that the PSMA3 C-terminal region is critical for 26S proteasome integrity.
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Affiliation(s)
- Shirel Steinberger
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Julia Adler
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
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Li C, Wang Z, Wei B, Liu Z, Li B, Kang H, Wang J, Liu J, Wang Q, Guo H, Wu X, Liu N, Luo J. Upregulation of ROBO3 promotes proliferation, migration and adhesion of AML cells and affects the survival of AML patients. Biochem Biophys Res Commun 2023; 661:1-9. [PMID: 37084487 DOI: 10.1016/j.bbrc.2023.04.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/23/2023]
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, which is the most common and severe acute leukemia in adults. Its occurrence, development and prognosis are affected by many factors, and more research is still needed to further guide its treatment. Here, we found that roundabout3 (ROBO3) was associated with poor prognosis in AML through bioinformatics analysis. We then found that overexpression of ROBO3 promoted AML cell proliferation, adhesion and migration while knockdown of ROBO3 had opposite effects. We subsequently found that ROBO3 regulated CD34 expression in AML cells, and this regulatory effect may be achieved through the Hippo-YAP pathway. The inhibitors of this pathway, K-975 and verteporfin, showed an inhibitory effect on AML cells with high ROBO3 expression. ROBO3 was also found to be significantly increased in bone marrow samples from AML patients. Our research indicates that ROBO3 plays an important role in the development of AML, which suggests that ROBO3 can be a prognostic biomarker and potential therapeutic target for AML.
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Affiliation(s)
- Chaonan Li
- Department of Hematology, Key Laboratory of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China; Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Zhen Wang
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China
| | - Binghui Wei
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zechen Liu
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Bei Li
- Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Hening Kang
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Jue Wang
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Junle Liu
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Qingyu Wang
- College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China
| | - Hongming Guo
- Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Xiaoli Wu
- Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Na Liu
- Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Jianmin Luo
- Department of Hematology, Key Laboratory of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
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9
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Ghosh I, Khalil MI, Mirza R, King J, Olatunde D, De Benedetti A. NEK1-Mediated Phosphorylation of YAP1 Is Key to Prostate Cancer Progression. Biomedicines 2023; 11:biomedicines11030734. [PMID: 36979713 PMCID: PMC10045622 DOI: 10.3390/biomedicines11030734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/13/2023] [Accepted: 02/20/2023] [Indexed: 03/04/2023] Open
Abstract
The key to preventing mCRPC progression is understanding how androgen-dependent PCa cells progress to independence and modify their transcriptional repertoire accordingly. We recently identified a novel axis of the Hippo pathway characterized by the sequential kinase cascade induced by androgen deprivation, AR−>TLK1B>NEK1>pYAP1-Y407, leading to CRPC adaptation. Phosphorylation of YAP1-Y407 increases upon ADT or induction of DNA damage, correlated with the known increase in NEK1 expression/activity, and this is suppressed in the Y407F mutant. Dominant expression of YAP1-Y407F in Hek293 cells reprograms the YAP1-mediated transcriptome to reduce TEAD- and p73-regulated gene expression and mediates sensitivity to MMC. NEK1 haploinsufficient TRAMP mice display reduced YAP1 expression and, if castrated, fail to progress to overt prostate carcinomas, even while displaying reduced E-Cadherin (E-Cad) expression in hyperplastic ductules. YAP1 overexpression, but not the Y407F mutant, transforms LNCaP cells to androgen-independent growth with a mesenchymal morphology. Immunohistochemical examination of prostate cancer biopsies revealed that the pYAP1-Y407 nuclear signal is low in samples of low-grade cancer but elevated in high GS specimens. We also found that J54, a pharmacological inhibitor of the TLK1>NEK1>YAP1 nexus leading to degradation of YAP1, can suppress the transcriptional reprogramming of LNCaP cells to androgen-independent growth and EMT progression, even when YAP1-WT is overexpressed.
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Affiliation(s)
- Ishita Ghosh
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Md Imtiaz Khalil
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Rusella Mirza
- Department of Pathology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Judy King
- Department of Pathology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Damilola Olatunde
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Shreveport, Shreveport, LA 71103, USA
- Correspondence:
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10
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Mohapatra T, Dixit M. IQ Motif Containing GTPase Activating Proteins (IQGAPs), A-Kinase Anchoring Proteins (AKAPs) and Kinase Suppressor of Ras Proteins (KSRs) in Scaffolding Oncogenic Pathways and Their Therapeutic Potential. ACS OMEGA 2022; 7:45837-45848. [PMID: 36570181 PMCID: PMC9773950 DOI: 10.1021/acsomega.2c05505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/18/2022] [Indexed: 06/17/2023]
Abstract
Scaffolding proteins colocalize interacting partners on their surface and facilitate complex formation. They have multiple domains and motifs, which provide binding sites for various molecules. This property of scaffolding proteins helps in the orderly transduction of signals. Abnormal signal transduction is frequently observed in cancers, which can also be attributed to the altered functionality of scaffolding proteins. IQ motif containing GTPase activating proteins (IQGAPs), kinase suppressor of Ras (KSR), and A-kinase anchoring proteins (AKAPs) tether oncogenic pathways RAS/RAF/MEK/ERK, PI3K/AKT, Hippo, Wnt, and CDC42/RAC to them. Scaffolding proteins are attractive drug targets as they are the controlling hub for multiple pathways and regulate crosstalk between them. The first part of this review describes the human scaffolding proteins known to play a role in oncogenesis, pathways altered by them, and the impact on oncogenic processes. The second part provides information on the therapeutic potential of scaffolding proteins and future possibilities. The information on the explored and unexplored areas of the therapeutic potential of scaffolding proteins will be equally helpful for biologists and chemists.
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Affiliation(s)
- Talina Mohapatra
- National
Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha 752050, India
- Homi
Bhabha National Institute, Training School
Complex, Anushaktinagar, Mumbai 400094, India
| | - Manjusha Dixit
- National
Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha 752050, India
- Homi
Bhabha National Institute, Training School
Complex, Anushaktinagar, Mumbai 400094, India
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11
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Wu QQ, Yao Q, Hu TT, Wan Y, Xie QW, Zhao JH, Yuan Y, Tang QZ. Tax1 banding protein 1 exacerbates heart failure in mice by activating ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis. Acta Pharmacol Sin 2022; 43:2562-2572. [PMID: 35948751 PMCID: PMC9525615 DOI: 10.1038/s41401-022-00950-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/26/2022] [Indexed: 11/09/2022]
Abstract
Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.
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Affiliation(s)
- Qing-Qing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qi Yao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Tong-Tong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Ying Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qing-Wen Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Jin-Hua Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Yuan Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China.
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12
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Lu X, Xu H, Xu J, Lu S, You S, Huang X, Zhang N, Zhang L. The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response. Front Physiol 2022; 13:968927. [PMID: 36091384 PMCID: PMC9458852 DOI: 10.3389/fphys.2022.968927] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/21/2022] [Indexed: 11/24/2022] Open
Abstract
E3 ubiquitin ligases, an important part of ubiquitin proteasome system, catalyze the covalent binding of ubiquitin to target substrates, which plays a role in protein ubiquitination and regulates different biological process. DNA damage response (DDR) is induced in response to DNA damage to maintain genome integrity and stability, and this process has crucial significance to a series of cell activities such as differentiation, apoptosis, cell cycle. The NEDD4 family, belonging to HECT E3 ubiquitin ligases, is reported as regulators that participate in the DDR process by recognizing different substrates. In this review, we summarize recent researches on NEDD4 family members in the DDR and discuss the roles of NEDD4 family members in the cascade reactions induced by DNA damage. This review may contribute to the further study of pathophysiology for certain diseases and pharmacology for targeted drugs.
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Affiliation(s)
- Xinxin Lu
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Haiqi Xu
- Department of Hematology, General Hospital of PLA Northern Theater Command, Shenyang, LN, China
| | - Jiaqi Xu
- Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Saien Lu
- Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Shilong You
- Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Xinyue Huang
- Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Naijin Zhang
- Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
| | - Lijun Zhang
- Department of Hematology, the First Affiliated Hospital of China Medical University, Shenyang, LN, China
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13
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Strobelt R, Adler J, Paran N, Yahalom-Ronen Y, Melamed S, Politi B, Shulman Z, Schmiedel D, Shaul Y. Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism. Sci Rep 2022; 12:5758. [PMID: 35388061 PMCID: PMC8984672 DOI: 10.1038/s41598-022-09664-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/21/2022] [Indexed: 12/15/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. More than 274 million individuals have suffered from COVID-19 and over five million people have died from this disease so far. Therefore, there is an urgent need for therapeutic drugs. Repurposing FDA approved drugs should be favored since evaluation of safety and efficacy of de-novo drug design are both costly and time consuming. We report that imatinib, an Abl tyrosine kinase inhibitor, robustly decreases SARS-CoV-2 infection and uncover a mechanism of action. We show that imatinib inhibits the infection of SARS-CoV-2 and its surrogate lentivector pseudotype. In latter, imatinib inhibited both routes of viral entry, endocytosis and membrane-fusion. We utilized a system to quantify in real-time cell-cell membrane fusion mediated by the SARS-CoV-2 surface protein, Spike, and its receptor, hACE2, to demonstrate that imatinib inhibits this process in an Abl1 and Abl2 independent manner. Furthermore, cellular thermal shift assay revealed a direct imatinib-Spike interaction that affects Spike susceptibility to trypsin digest. Collectively, our data suggest that imatinib inhibits Spike mediated viral entry by an off-target mechanism. These findings mark imatinib as a promising therapeutic drug in inhibiting the early steps of SARS-CoV-2 infection.
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Affiliation(s)
- Romano Strobelt
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Julia Adler
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Nir Paran
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Yfat Yahalom-Ronen
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Sharon Melamed
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Boaz Politi
- Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona, Israel
| | - Ziv Shulman
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Dominik Schmiedel
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
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14
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Xiao Y, Dong J. The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Cancers (Basel) 2021; 13:cancers13246214. [PMID: 34944834 PMCID: PMC8699626 DOI: 10.3390/cancers13246214] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/07/2021] [Accepted: 12/08/2021] [Indexed: 01/25/2023] Open
Abstract
Simple Summary Cancer is increasingly viewed as a cell cycle disease in that the dysregulation of the cell cycle machinery is a common feature in cancer. The Hippo signaling pathway consists of a core kinase cascade as well as extended regulators, which together control organ size and tissue homeostasis. The aberrant expression of cell cycle regulators and/or Hippo pathway components contributes to cancer development, and for this reason, we specifically focus on delineating the roles of the Hippo pathway in the cell cycle. Improving our understanding of the Hippo pathway from a cell cycle perspective could be used as a powerful weapon in the cancer battlefield. Abstract Cell cycle progression is an elaborate process that requires stringent control for normal cellular function. Defects in cell cycle control, however, contribute to genomic instability and have become a characteristic phenomenon in cancers. Over the years, advancement in the understanding of disrupted cell cycle regulation in tumors has led to the development of powerful anti-cancer drugs. Therefore, an in-depth exploration of cell cycle dysregulation in cancers could provide therapeutic avenues for cancer treatment. The Hippo pathway is an evolutionarily conserved regulator network that controls organ size, and its dysregulation is implicated in various types of cancers. Although the role of the Hippo pathway in oncogenesis has been widely investigated, its role in cell cycle regulation has not been comprehensively scrutinized. Here, we specifically focus on delineating the involvement of the Hippo pathway in cell cycle regulation. To that end, we first compare the structural as well as functional conservation of the core Hippo pathway in yeasts, flies, and mammals. Then, we detail the multi-faceted aspects in which the core components of the mammalian Hippo pathway and their regulators affect the cell cycle, particularly with regard to the regulation of E2F activity, the G1 tetraploidy checkpoint, DNA synthesis, DNA damage checkpoint, centrosome dynamics, and mitosis. Finally, we briefly discuss how a collective understanding of cell cycle regulation and the Hippo pathway could be weaponized in combating cancer.
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Affiliation(s)
| | - Jixin Dong
- Correspondence: ; Tel.: +402-559-5596; Fax: +402-559-4651
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15
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Lim YX, Lin H, Seah SH, Lim YP. Reciprocal Regulation of Hippo and WBP2 Signalling-Implications in Cancer Therapy. Cells 2021; 10:cells10113130. [PMID: 34831354 PMCID: PMC8625973 DOI: 10.3390/cells10113130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/08/2021] [Accepted: 11/08/2021] [Indexed: 11/23/2022] Open
Abstract
Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.
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Affiliation(s)
- Yvonne Xinyi Lim
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore 119077, Singapore; (Y.X.L.); (H.L.); (S.H.S.)
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore
| | - Hexian Lin
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore 119077, Singapore; (Y.X.L.); (H.L.); (S.H.S.)
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore
| | - Sock Hong Seah
- Integrative Sciences and Engineering Programme, National University of Singapore, Singapore 119077, Singapore; (Y.X.L.); (H.L.); (S.H.S.)
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Yoon Pin Lim
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore
- Correspondence:
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16
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Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase. Sci Rep 2021; 11:20974. [PMID: 34697383 PMCID: PMC8546089 DOI: 10.1038/s41598-021-00439-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 10/12/2021] [Indexed: 12/17/2022] Open
Abstract
Our lab has previously demonstrated Riluzole to be an effective drug in inhibiting proliferation and inducing apoptosis in both human and mouse osteosarcoma. Yes-associated protein is a transcription co-activator, known to be involved in cell proliferation or apoptosis depending on its protein partner. In the present study we investigated the role of YAP in apoptosis in osteosarcoma, we hypothesized that YAP may be activated by Riluzole to induce apoptosis in osteosarcoma. By knocking down the expression of YAP, we have demonstrated that Riluzole failed to induce apoptosis in YAP deficient osteosarcoma cells. Riluzole caused translocation of YAP from the cytoplasm to the nucleus, indicating YAP’s role in apoptosis. Both Riluzole-induced phosphorylation of YAP at tyrosine 357 and Riluzole-induced apoptosis were blocked by inhibitors of c-Abl kinase. In addition, knockdown of c-Abl kinase prevented Riluzole-induced apoptosis in LM7 cells. We further demonstrated that Riluzole promoted interaction between YAP and p73, while c-Abl kinase inhibitors abolished the interaction. Subsequently, we demonstrated that Riluzole enhanced activity of the Bax promoter in a luciferase reporter assay and enhanced YAP/p73 binding on endogenous Bax promoter in a ChIP assay. Our data supports a novel mechanism in which Riluzole activates c-Abl kinase to regulate pro-apoptotic activity of YAP in osteosarcoma.
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17
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Zhu M, Peng R, Liang X, Lan Z, Tang M, Hou P, Song JH, Mak CSL, Park J, Zheng SE, Huang A, Ma X, Chen R, Chang Q, Logothetis CJ, Jain AK, Lin SH, Katayama H, Hanash S, Wang G. P4HA2-induced prolyl hydroxylation suppresses YAP1-mediated prostate cancer cell migration, invasion, and metastasis. Oncogene 2021; 40:6049-6056. [PMID: 34471235 PMCID: PMC8526415 DOI: 10.1038/s41388-021-02000-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 08/09/2021] [Accepted: 08/20/2021] [Indexed: 02/07/2023]
Abstract
Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1 led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2 led to an increase in cell migration and invasion, which was reversed upon Yap1 KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.
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Affiliation(s)
- Ming Zhu
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ruiqing Peng
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xin Liang
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhengdao Lan
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ming Tang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Pingping Hou
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jian H. Song
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Celia Sze Ling Mak
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jiwon Park
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shui-er Zheng
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ailing Huang
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xingdi Ma
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ruidong Chen
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Qing Chang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Christopher J. Logothetis
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Abhinav K. Jain
- Department of Epigenetics and Molecular Carcinogenesis & Epigenomics Profiling Core Facility, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sue-Hwa Lin
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hiroyuki Katayama
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Samir Hanash
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Guocan Wang
- Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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18
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Lopez-Hernandez A, Sberna S, Campaner S. Emerging Principles in the Transcriptional Control by YAP and TAZ. Cancers (Basel) 2021; 13:cancers13164242. [PMID: 34439395 PMCID: PMC8391352 DOI: 10.3390/cancers13164242] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/13/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary YAP and TAZ are transcriptional cofactors that integrate several upstream signals to generate context-dependent transcriptional responses. This requires extensive integration with epigenetic regulators and other transcription factors. The molecular and genomic characterization of YAP and TAZ nuclear function has broad implications both in physiological and pathological settings. Abstract Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.
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p53/p73 Protein Network in Colorectal Cancer and Other Human Malignancies. Cancers (Basel) 2021; 13:cancers13122885. [PMID: 34207603 PMCID: PMC8227208 DOI: 10.3390/cancers13122885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The p53 family of proteins comprises p53, p63, and p73, which share high structural and functional similarity. The two distinct promoters of each locus, the alternative splicing, and the alternative translation initiation sites enable the generation of numerous isoforms with different protein-interacting domains and distinct activities. The co-expressed p53/p73 isoforms have significant but distinct roles in carcinogenesis. Their activity is frequently impaired in human tumors including colorectal carcinoma due to dysregulated expression and a dominant-negative effect accomplished by some isoforms and p53 mutants. The interactions between isoforms are particularly important to understand the onset of tumor formation, progression, and therapeutic response. The understanding of the p53/p73 network can contribute to the development of new targeted therapies. Abstract The p53 tumor suppressor protein is crucial for cell growth control and the maintenance of genomic stability. Later discovered, p63 and p73 share structural and functional similarity with p53. To understand the p53 pathways more profoundly, all family members should be considered. Each family member possesses two promoters and alternative translation initiation sites, and they undergo alternative splicing, generating multiple isoforms. The resulting isoforms have important roles in carcinogenesis, while their expression is dysregulated in several human tumors including colorectal carcinoma, which makes them potential targets in cancer treatment. Their activities arise, at least in part, from the ability to form tetramers that bind to specific DNA sequences and activate the transcription of target genes. In this review, we summarize the current understanding of the biological activities and regulation of the p53/p73 isoforms, highlighting their role in colorectal tumorigenesis. The analysis of the expression patterns of the p53/p73 isoforms in human cancers provides an important step in the improvement of cancer therapy. Furthermore, the interactions among the p53 family members which could modulate normal functions of the canonical p53 in tumor tissue are described. Lastly, we emphasize the importance of clinical studies to assess the significance of combining the deregulation of different members of the p53 family to define the outcome of the disease.
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Omran Z, H. Dalhat M, Abdullah O, Kaleem M, Hosawi S, A Al-Abbasi F, Wu W, Choudhry H, Alhosin M. Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors. Cancers (Basel) 2021; 13:1916. [PMID: 33921128 PMCID: PMC8071514 DOI: 10.3390/cancers13081916] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 01/11/2023] Open
Abstract
The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.
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Affiliation(s)
- Ziad Omran
- College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia; (Z.O.); (O.A.)
| | - Mahmood H. Dalhat
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
| | - Omeima Abdullah
- College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia; (Z.O.); (O.A.)
| | - Mohammed Kaleem
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
| | - Salman Hosawi
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
| | - Fahd A Al-Abbasi
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
| | - Wei Wu
- Department of Medicine, University of California, San Francisco, CA 94143, USA;
| | - Hani Choudhry
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
| | - Mahmoud Alhosin
- King Fahd Medical Research Center, Cancer and Mutagenesis Unit, Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia; (M.H.D.); (M.K.); (S.H.); (F.A.A.-A.); (H.C.)
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21
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Reuven N, Adler J, Myers N, Shaul Y. CRISPR Co-Editing Strategy for Scarless Homology-Directed Genome Editing. Int J Mol Sci 2021; 22:3741. [PMID: 33916763 PMCID: PMC8038335 DOI: 10.3390/ijms22073741] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/23/2021] [Accepted: 03/26/2021] [Indexed: 12/27/2022] Open
Abstract
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 has revolutionized genome editing by providing a simple and robust means to cleave specific genomic sequences. However, introducing templated changes at the targeted site usually requires homology-directed repair (HDR), active in only a small subset of cells in culture. To enrich for HDR-dependent edited cells, we employed a co-editing strategy, editing a gene of interest (GOI) concomitantly with rescuing an endogenous pre-made temperature-sensitive (ts) mutation. By using the repair of the ts mutation as a selectable marker, the selection is "scarless" since editing restores the wild-type (wt) sequence. As proof of principle, we used HEK293 and HeLa cells with a ts mutation in the essential TAF1 gene. CRISPR co-editing of TAF1ts and a GOI resulted in up to 90% of the temperature-resistant cells bearing the desired mutation in the GOI. We used this system to insert large cassettes encoded by plasmid donors and smaller changes encoded by single-stranded oligonucleotide donors (ssODN). Of note, among the genes we edited was the introduction of a T35A mutation in the proteasome subunit PSMB6, which eliminates its caspase-like activity. The edited cells showed a specific reduction in this activity, demonstrating this system's utility in generating cell lines with biologically relevant mutations in endogenous genes. This approach offers a rapid, efficient, and scarless method for selecting genome-edited cells requiring HDR.
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Affiliation(s)
- Nina Reuven
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel; (J.A.); (N.M.)
| | | | | | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel; (J.A.); (N.M.)
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Szulzewsky F, Holland EC, Vasioukhin V. YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance. Dev Biol 2021; 475:205-221. [PMID: 33428889 DOI: 10.1016/j.ydbio.2020.12.018] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/14/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.
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Affiliation(s)
- Frank Szulzewsky
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
| | - Eric C Holland
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA; Seattle Tumor Translational Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | - Valeri Vasioukhin
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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Dong T, Yuan Y, Xiang X, Sang S, Shen H, Wang L, Yang C, Li F, Li H, Zheng S. High cytoplasmic YAP1 expression predicts a poor prognosis in patients with colorectal cancer. PeerJ 2020; 8:e10397. [PMID: 33240680 PMCID: PMC7680625 DOI: 10.7717/peerj.10397] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/29/2020] [Indexed: 12/19/2022] Open
Abstract
Purpose Yes associated protein 1 (YAP1), which is a standout amongst the most essential effectors of the Hippo pathway, assumes a vital part in a few kinds of cancer. However, whether YAP1 is an oncogene in CRC (colorectal cancer) remains controversial, and the association between the subcellular localization of YAP1 and clinical implications in CRC remains unknown. Patients and methods In this study, we investigated the subcellular localization of YAP1 in CRC cells by immunohistochemistry and then associate these findings with clinical information in a large CRC cohort with 919 CRC patients. Results The results show that CRC tissues has a significant higher expression of cytoplasmic YAP1 compared to adjacent normal tissues (all P < 0.001). Cytoplasmic YAP1 expression was significantly associated with the number of lymph nodes removed and differentiation grade (all P < 0.001). Furthermore, after correcting confounding variables, for example, TNM stage and differentiation grade, the multivariate Cox analysis confirmed cytoplasmic YAP1-high subgroup had a significant shorter DFS (HR = 3.255; 95% CI [2.290-4.627]; P < 0.001) and DSS (HR = 4.049; 95% CI [2.400-6.830]; P < 0.001) than cytoplasmic YAP1-low subgroup. High cytoplasmic YAP1 expression is associated with a worse survival in stage III CRC patients who received chemotherapy. Conclusion Cytoplasmic YAP1 could be could be utilized as a prognosis factor in CRC patients, and may be an indicator of whether certain patients population could benefit from postoperative chemotherapy.
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Affiliation(s)
- Tianqi Dong
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Yuncang Yuan
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Xudong Xiang
- Department of Thoracic Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shuping Sang
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Hao Shen
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Lei Wang
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Chunyan Yang
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Fangfang Li
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Hongliang Li
- School of Medicine, Yunnan University, Kunming, Yunnan, China
| | - Shangyong Zheng
- School of Medicine, Yunnan University, Kunming, Yunnan, China
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Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. There are few cures for ADPKD, although many researchers are trying to find a cure. The Hippo signaling pathway regulates organ growth and cell proliferation. Transcriptional coactivator with PDZ-binding motif (TAZ) is a Hippo signaling effector. In this study, we demonstrated that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis. Endo IWR1 treatment, which inhibited β-catenin activity via AXIN stabilization, reduced cyst growth in an ADPKD model. Our findings provide a potential therapeutic target against ADPKD and would be important for clinical translation. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated β-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing β-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with β-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1–TAZ–Wnt–β-catenin–c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.
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Wen Z, Wang Y, Qi S, Ma M, Li J, Yu FX. Regulation of TP73 transcription by Hippo-YAP signaling. Biochem Biophys Res Commun 2020; 531:96-104. [PMID: 32773110 DOI: 10.1016/j.bbrc.2020.07.132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 11/19/2022]
Abstract
Yes-associated protein (YAP) is a key downstream effector of the highly conserved Hippo signaling pathway, which regulates organ size, regeneration and tumorigenesis. Known classically to function as a transcriptional co-activator, YAP interacts with TEA domain transcription factors (TEAD1-4) to induce expression of target genes. However, a number of genes are repressed upon YAP activation, suggesting a transcriptional repressor role of YAP. Here, we report that TP73 is a direct target gene of YAP, and its transcription is repressed by YAP in a TEAD-independent manner. On the other hand, WW domains of YAP are indispensable for the regulation of TP73 expression, which may recruit YAP to TP73 gene though interaction with ZEB1 and/or RUNX2, two transcriptional repressors. Moreover, YAP-mediated repression of TP73 promotes cancer cell survival in the presence of chemotherapeutic agents, suggesting YAP-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies.
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Affiliation(s)
- Zichao Wen
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Wang
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sixian Qi
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mingyue Ma
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Li
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fa-Xing Yu
- Institute of Pediatrics, Children's Hospital of Fudan University and the Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
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p73: From the p53 shadow to a major pharmacological target in anticancer therapy. Pharmacol Res 2020; 162:105245. [PMID: 33069756 DOI: 10.1016/j.phrs.2020.105245] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 02/06/2023]
Abstract
p73, along with p53 and p63, belongs to the p53 family of transcription factors. Besides the p53-like tumor suppressive activities, p73 has unique roles, namely in neuronal development and differentiation. In addition, the TP73 gene is rarely mutated in tumors. This makes p73 a highly appealing therapeutic target, particularly towards cancers with a null or disrupted p53 pathway. Distinct isoforms are transcribed from the TP73 locus either with (TAp73) and without (ΔNp73) the N-terminal transactivation domain. Conversely to TA tumor suppressors, ΔN proteins exhibit oncogenic properties by inhibiting p53 and TA protein functions. As such, p73 isoforms compose a puzzled and challenging regulatory pathway. This state-of-the-art review affords an update overview on p73 structure, biological functions and pharmacological regulation. Importantly, it addresses the relevance of p73 isoforms in carcinogenesis, highlighting their potential as drug targets in anticancer therapy. A critical discussion of major pharmacological approaches to promote p73 tumor suppressive activities, with relevant survival outcomes for cancer patients, is also provided.
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Cao L, Yao M, Sasano H, Sun PL, Gao H. YAP increases response to Trastuzumab in HER2-positive Breast Cancer by enhancing P73-induced apoptosis. J Cancer 2020; 11:6748-6759. [PMID: 33046997 PMCID: PMC7545685 DOI: 10.7150/jca.48535] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 09/10/2020] [Indexed: 12/15/2022] Open
Abstract
The role of the Yes-associated protein (YAP) in oncogenesis and progression of breast cancer remains controversial. Meanwhile, development of therapeutic resistance to trastuzumab, a common breast cancer treatment administered after chemotherapy, is a significant challenge in the treatment of HER2-positive breast cancer. We, therefore, analyzed the role of YAP in trastuzumab resistance in HER2-positive-breast carcinoma cells in vitro and evaluated the status of YAP and related proteins in patient-derived breast carcinoma tissues by immunohistochemistry. YAP expression was observed in both BT474-TS (trastuzumab-sensitive) and BT474-TR (trastuzumab-resistant) cells. Treatment with trastuzumab increased expression of nuclear-YAP (N-YAP) in BT474-TS cells, whereas BT474-TR cells showed a decrease in N-YAP expression following trastuzumab treatment. YAP silencing significantly reduced trastuzumab-induced inhibitory effects in BT474-TS cells. YAP-silenced cells also showed decreased apoptosis and significantly lower p73 levels following trastuzumab treatment. Combined protein kinase B (AKT) inhibitor-trastuzumab treatment significantly inhibited BT474-TR cell proliferation, resulting in increased N-YAP and p73 expression, as well as apoptosis. In both paclitaxel, doxorubicin and cyclophosphamide (TAC)-treated, and docetaxel, carboplatin, and trastuzumab (TCbH)-treated groups; the pathological complete response (pCR) ratios were inversely correlated with p-AKT status in biopsy specimens, while YAP and p73 status were positively correlated with the pCR ratio in the biopsy specimens of the TCbH group. Our results show that YAP is involved in trastuzumab resistance in HER2-positive breast carcinoma cells and that YAP and AKT may be developed as prognostic markers of neoadjuvant trastuzumab therapy in patients with HER2-positive breast cancer.
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Affiliation(s)
- Lanqing Cao
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Min Yao
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Hironobu Sasano
- Department of Pathology, Tohoku University School of Medicine and Tohoku University Hospital, 2-1 Seiryo-machi, Aoba-Ku, Sendai, Miyagi 980-8575, Japan
| | - Ping-Li Sun
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Hongwen Gao
- Department of Pathology, The Second Hospital of Jilin University, Changchun, Jilin 130041, China
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The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing. Cancers (Basel) 2020; 12:cancers12092717. [PMID: 32971841 PMCID: PMC7563196 DOI: 10.3390/cancers12092717] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 02/07/2023] Open
Abstract
p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the 'guardian of the genome' and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.
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Jiang Y, Zhang J, Guo D, Zhang C, Hong L, Huang H, Liu H. Entire ABL1 Gene Deletion Without BCR/ABL1 Rearrangement in a Female Patient with B-Cell Precursor Acute Lymphoblastic Leukemia. Onco Targets Ther 2020; 13:783-790. [PMID: 32158229 PMCID: PMC6986541 DOI: 10.2147/ott.s238336] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 01/09/2020] [Indexed: 11/23/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by lymphocytic B-line or T-line cells abnormally proliferating in the bone marrow or extramedullary sites. BCR/ABL1 fusion protein in patients with ALL accounts for acts in 15-30% of B-lineage ALL cases, usually in adolescence. However, entire ABL1 gene deletion without BCR/ABL1 rearrangement is a rare phenomenon in ALL patients. Here we describe the first case of entire ABL1 gene deletion without BCR/ABL1 rearrangement in a female B-ALL patient. Relevant literature is reviewed to explain the association between ABL1 deletion and the pathogenesis/prognosis of this disease. ABL gene deletion can repress the activation of p53 and p73, and disrupt TGF-β signaling pathway to allow malignant cells to invade the normal tissue. The clinical significance of ABL gene deletion needs to be further explored.
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Affiliation(s)
- Yijing Jiang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Jie Zhang
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong 226361, Jiangsu, People's Republic of China
| | - Dan Guo
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Chenlu Zhang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Lemin Hong
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Hongming Huang
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
| | - Haiyan Liu
- Department of Hematology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China
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NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma. Cell Commun Signal 2019; 17:168. [PMID: 31842909 PMCID: PMC6915971 DOI: 10.1186/s12964-019-0491-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/26/2019] [Indexed: 12/11/2022] Open
Abstract
Background Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. Methods Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. Results We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. Conclusions Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.
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31
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Bernassola F, Chillemi G, Melino G. HECT-Type E3 Ubiquitin Ligases in Cancer. Trends Biochem Sci 2019; 44:1057-1075. [DOI: 10.1016/j.tibs.2019.08.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 08/13/2019] [Accepted: 08/23/2019] [Indexed: 12/30/2022]
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Molina-Castro SE, Tiffon C, Giraud J, Boeuf H, Sifre E, Giese A, Belleannée G, Lehours P, Bessède E, Mégraud F, Dubus P, Staedel C, Varon C. The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa. Cell Mol Gastroenterol Hepatol 2019; 9:257-276. [PMID: 31669263 PMCID: PMC6957828 DOI: 10.1016/j.jcmgh.2019.10.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context. METHODS Hippo, EMT, and intestinal metaplasia marker expression were investigated by transcriptomic and immunostaining analyses in human gastric AGS and MKN74 and nongastric immortalized RPE1 and HMLE epithelial cell lines challenged by H pylori, and on gastric tissues of infected patients and mice. LATS2 and YAP1 were silenced using small interfering RNAs. A transcriptional enhanced associated domain (TEAD) reporter assay was used. Cell proliferation and invasion were evaluated. RESULTS LATS2 and YAP1 appear co-overexpressed in the infected mucosa, especially in gastritis and intestinal metaplasia. H pylori via CagA stimulates LATS2 and YAP1 in a coordinated biphasic pattern, characterized by an early transient YAP1 nuclear accumulation and stimulated YAP1/TEAD transcription, followed by nuclear LATS2 up-regulation leading to YAP1 phosphorylation and targeting for degradation. LATS2 and YAP1 reciprocally positively regulate each other's expression. Loss-of-function experiments showed that LATS2 restricts H pylori-induced EMT marker expression, invasion, and intestinal metaplasia, supporting a role of LATS2 in maintaining the epithelial phenotype of gastric cells and constraining H pylori-induced preneoplastic changes. CONCLUSIONS H pylori infection engages a number of signaling cascades that alienate mucosa homeostasis, including the Hippo LATS2/YAP1/TEAD pathway. In the host-pathogen conflict, which generates an inflammatory environment and perturbations of the epithelial turnover and differentiation, Hippo signaling appears as a protective pathway, limiting the loss of gastric epithelial cell identity that precedes gastric carcinoma development.
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Affiliation(s)
- Silvia Elena Molina-Castro
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,University of Costa Rica, San José, Costa Rica
| | - Camille Tiffon
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France
| | - Julie Giraud
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France
| | - Hélène Boeuf
- INSERM, UMR1026, Bioingénierie tissulaire (BioTis), University of Bordeaux, Bordeaux, France
| | - Elodie Sifre
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France
| | - Alban Giese
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France
| | | | - Philippe Lehours
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
| | - Emilie Bessède
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
| | - Francis Mégraud
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
| | - Pierre Dubus
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
| | - Cathy Staedel
- INSERM, UMR1212, University of Bordeaux, Bordeaux, France,Cathy Staedel, PhD, INSERM U1212, “ARN: Régulations naturelle et artificielle” (ARNA)-Unités Mixtes de Recherche (UMR) Centre national de la recherche scientifique (CNRS) 5320, University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France. fax: +33 5 57 57 10 15.
| | - Christine Varon
- INSERM, UMR1053, Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France,Correspondence Address correspondence to: Christine Varon, PhD, INSERM U1053 Bordeaux Research in Translational Oncology (BaRITOn), University of Bordeaux, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France. fax: +33 5 56 79 60 18.
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Reuven N, Adler J, Broennimann K, Myers N, Shaul Y. Recruitment of DNA Repair MRN Complex by Intrinsically Disordered Protein Domain Fused to Cas9 Improves Efficiency of CRISPR-Mediated Genome Editing. Biomolecules 2019; 9:E584. [PMID: 31597252 PMCID: PMC6843829 DOI: 10.3390/biom9100584] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/02/2019] [Accepted: 10/05/2019] [Indexed: 12/11/2022] Open
Abstract
CRISPR/Cas9 is a powerful tool for genome editing in cells and organisms. Nevertheless, introducing directed templated changes by homology-directed repair (HDR) requires the cellular DNA repair machinery, such as the MRN complex (Mre11/Rad50/Nbs1). To improve the process, we tailored chimeric constructs of Cas9, in which SpCas9 was fused at its N- or C-terminus to a 126aa intrinsically disordered domain from HSV-1 alkaline nuclease (UL12) that recruits the MRN complex. The chimeric Cas9 constructs were two times more efficient in homology-directed editing of endogenous loci in tissue culture cells. This effect was dependent upon the MRN-recruiting activity of the domain and required lower amounts of the chimeric Cas9 in comparison with unmodified Cas9. The new constructs improved the yield of edited cells when making endogenous point mutations or inserting small tags encoded by oligonucleotide donor DNA (ssODN), and also with larger insertions encoded by plasmid DNA donor templates. Improved editing was achieved with both transfected plasmid-encoded Cas9 constructs as well as recombinant Cas9 protein transfected as ribonucleoprotein complexes. Our strategy was highly efficient in restoring a genetic defect in a cell line, exemplifying the possible implementation of our strategy in gene therapy. These constructs provide a simple approach to improve directed editing.
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Affiliation(s)
- Nina Reuven
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
| | - Julia Adler
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
| | - Karin Broennimann
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
| | - Nadav Myers
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
| | - Yosef Shaul
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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Raj N, Bam R. Reciprocal Crosstalk Between YAP1/Hippo Pathway and the p53 Family Proteins: Mechanisms and Outcomes in Cancer. Front Cell Dev Biol 2019; 7:159. [PMID: 31448276 PMCID: PMC6695833 DOI: 10.3389/fcell.2019.00159] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/29/2019] [Indexed: 12/16/2022] Open
Abstract
The YAP1/Hippo and p53 pathways are critical protectors of genome integrity in response to DNA damage. Together, these pathways secure cellular adaptation and maintain overall tissue integrity through transcriptional re-programing downstream of various environmental and biological cues generated during normal tissue growth, cell proliferation, and apoptosis. Genetic perturbations in YAP1/Hippo and p53 pathways are known to contribute to the cells’ ability to turn rogue and initiate tumorigenesis. The Hippo and p53 pathways cooperate on many levels and are closely coordinated through multiple molecular components of their signaling pathways. Several functional and physical interactions have been reported to occur between YAP1/Hippo pathway components and the three p53 family members, p53, p63, and p73. Primarily, functional status of p53 family proteins dictates the subcellular localization, protein stability and transcriptional activity of the core component of the Hippo pathway, Yes-associated protein 1 (YAP1). In this review, we dissect the critical points of crosstalk between the YAP1/Hippo pathway components, with a focus on YAP1, and the p53 tumor suppressor protein family. For each p53 family member, we discuss the biological implications of their interaction with Hippo pathway components in determining cell fate under the conditions of tissue homeostasis and cancer pathogenesis.
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Affiliation(s)
- Nitin Raj
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, United States
| | - Rakesh Bam
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, United States
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Naseer F, Saleem M. Epigenetic modification in the expression of p73 p73 - epigenetic target for anticancer therapy. Oncol Rev 2019; 13:421. [PMID: 31410249 PMCID: PMC6661529 DOI: 10.4081/oncol.2019.421] [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: 03/14/2019] [Accepted: 06/10/2019] [Indexed: 11/22/2022] Open
Abstract
A p73 is a new member of p53 family of transcription factor, having two types. First is TAp73, transcriptionally active and expressed via upstream promoter as a tumor suppressor and vital apoptotic inductor, it also has a key role in cell cycle arrest/differentiation and Second is ΔNp73 that is transcriptionally inactive and expressed via downstream regulator as oncogenes. Both types are expressed in various isoforms, which originate from alternative splicing events at the C-terminus. Upon DNA damage, posttranslational modifications cause conformational changes in various amino acid residues via induction or inhibition of various proteins, which are present in the structural domains of p73. These modifications may cause up- or down-regulation of p73 expression levels, as well as alters the transcriptional activity and/or stability of the protein. In this review, we have made an effort to assemble all existing data regarding the role of p73, its modification and after effects in cancer.
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Affiliation(s)
- Faiza Naseer
- Shifa College of Pharmaceutical Sciences, Shifa Tameer e Millat University, Islamabad, Pakistan
| | - Mohammad Saleem
- Faculty of Pharmaceutical Sciences, Punjab University, Lahore, Pakistan
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Shreberk-Shaked M, Oren M. New insights into YAP/TAZ nucleo-cytoplasmic shuttling: new cancer therapeutic opportunities? Mol Oncol 2019; 13:1335-1341. [PMID: 31050214 PMCID: PMC6547617 DOI: 10.1002/1878-0261.12498] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/29/2019] [Accepted: 05/02/2019] [Indexed: 12/14/2022] Open
Abstract
Yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ), the main effectors of the Hippo pathway, are emerging as important players in cancer biology and therapy response. The intracellular localization of YAP/TAZ is a key determinant in the regulation of their activity and their roles in signal transduction. This is particularly relevant for cancer: Aberrant nuclear localization of YAP and TAZ has been observed in numerous human cancers and may therefore represent an attractive target for cancer therapy. In this review, we describe the mechanisms that regulate the nucleo‐cytoplasmic shuttling of YAP/TAZ and their implications for cancer, and discuss how the new insights about this process may pave the way for novel therapeutic strategies.
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Affiliation(s)
| | - Moshe Oren
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
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Gupta R, Bhatt LK, Johnston TP, Prabhavalkar KS. Colon cancer stem cells: Potential target for the treatment of colorectal cancer. Cancer Biol Ther 2019; 20:1068-1082. [PMID: 31050577 DOI: 10.1080/15384047.2019.1599660] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Despite incessant research, colon cancer still is one of the most common causes of fatalities in both men and women worldwide. Also, nearly 50% of patients with colorectal cancer show tumor recurrence. Recent investigations have highlighted the involvement of colon cancer stem cells (CCSCs) in cancer relapse and chemoresistance. CCSCs deliver a significant protumorigenic niche through persistent overexpression of self-renewal capabilities. Moreover, CSCs cross network with stromal cells, immune infiltrates, and cyotokine-chemokine, which potentiate their aggressive proliferative potential. Targeting CCSCs through small molecule inhibitors, miRNAs, and monoclonal antibodies (mAbs) in in vivo studies has generated compelling evidence for the effectiveness of these various treatments. This review effectively compiles the role of CCSC surface markers and dysregulated and/or upregulated pathways in the pathogenesis of colorectal cancer that can be used to target CCSCs for effective colorectal cancer treatment.
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Affiliation(s)
- Riya Gupta
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
| | - Lokesh Kumar Bhatt
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
| | - Thomas P Johnston
- b Division of Pharmacology and Pharmaceutical Sciences , University of Missouri-Kansas City , Kansas City , MO , USA
| | - Kedar S Prabhavalkar
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
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Regulation of autoimmune disease by the E3 ubiquitin ligase Itch. Cell Immunol 2019; 340:103916. [PMID: 31126634 DOI: 10.1016/j.cellimm.2019.04.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 04/03/2019] [Indexed: 12/14/2022]
Abstract
Itch is a HECT type E3 ubiquitin ligase that is required to prevent the development of autoimmune disease in both mice and humans. Itch is expressed in most mammalian cell types, and, based on published data, it regulates many cellular pathways ranging from T cell differentiation to liver tumorigenesis. Since 1998, when Itch was first discovered, hundreds of publications have described mechanisms through which Itch controls various biologic activities in both immune and non-immune cells. Other studies have provided insight into how Itch catalytic activity is regulated. However, while autoimmunity is the primary clinical feature that occurs in both mice and humans lacking Itch, and Itch control of immune cell function has been well-studied, it remains unclear how Itch prevents the emergence of autoimmune disease. In this review, we explore recent discoveries that advance our understanding of how Itch regulates immune cell biology, and the extent to which these clarify how Itch prevents autoimmune disease. Additionally, we discuss how molecular regulators of Itch impact its ability to control these processes, as this may provide clues on how to therapeutically target Itch to treat patients with autoimmune disease.
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Mechanotransduction and Cytoskeleton Remodeling Shaping YAP1 in Gastric Tumorigenesis. Int J Mol Sci 2019; 20:ijms20071576. [PMID: 30934860 PMCID: PMC6480114 DOI: 10.3390/ijms20071576] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/14/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023] Open
Abstract
The essential role of Hippo signaling pathway in cancer development has been elucidated by recent studies. In the gastrointestinal tissues, deregulation of the Hippo pathway is one of the most important driving events for tumorigenesis. It is widely known that Yes-associated protein 1 (YAP1) and WW domain that contain transcription regulator 1 (TAZ), two transcriptional co-activators with a PDZ-binding motif, function as critical effectors negatively regulated by the Hippo pathway. Previous studies indicate the involvement of YAP1/TAZ in mechanotransduction by crosstalking with the extracellular matrix (ECM) and the F-actin cytoskeleton associated signaling network. In gastric cancer (GC), YAP1/TAZ functions as an oncogene and transcriptionally promotes tumor formation by cooperating with TEAD transcription factors. Apart from the classic role of Hippo-YAP1 cascade, in this review, we summarize the current investigations to highlight the prominent role of YAP1/TAZ as a mechanical sensor and responder under mechanical stress and address its potential prognostic and therapeutic value in GC.
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Zhang S, Wei Q, Yang Y, Qin H, Li X, Cai S, Ma Y. Loss of Yes-associated Protein Represents an Aggressive Subtype of Colorectal Cancer. J Cancer 2019; 10:689-696. [PMID: 30719167 PMCID: PMC6360423 DOI: 10.7150/jca.28333] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/27/2018] [Indexed: 01/15/2023] Open
Abstract
Background: Yes-associated protein (YAP) is a downstream effecter of Hippo signaling pathway, and has been linked to the initiation and development of colorectal cancer (CRC). However, the clinical significance of YAP in CRC remains controversial. This study was designed to investigate the clinical significance of YAP in CRC. Methods: We selected 206 eligible patients diagnosed with CRC from 2003 to 2007. Tissue microarray (TMA) blocks were made from 206 formalin-fixed paraffin-embedded CRC tissues and 158 corresponding normal colonic tissues. Using the TMA blocks, we performed immunohistochemical staining of YAP and assessed its expression status in different subcellular locations. The patients were divided into four groups according to the expression status of YAP in the cytoplasm and nucleus. Statistical analysis was performed to explore the correlation between YAP expression and clinicopathological features and overall survival (OS) in CRC patients. Results: Our results showed that both cytoplasmic YAP and nuclear YAP were overexpressed in CRC tissues compared to normal colonic tissues. Complete loss of YAP expression in CRC was significantly correlated with larger tumor size (p=0.023), proximal tumor location (p=0.038), higher tumor grade (p=0.022) and worse OS (p<0.001). Univariate and multivariate Cox regression analyses revealed that complete loss of YAP expression was an independent indicator of poor prognosis in CRC (p<0.001). Conclusions: Loss of YAP expression correlates with poor prognosis and may represent a subgroup with more aggressive biological features in CRC.
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Affiliation(s)
- Sheng Zhang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Qing Wei
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Yongzhi Yang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Huanlong Qin
- Department of GI Surgery, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yanlei Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
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Jamous A, Salah Z. WW-Domain Containing Protein Roles in Breast Tumorigenesis. Front Oncol 2018; 8:580. [PMID: 30619734 PMCID: PMC6300493 DOI: 10.3389/fonc.2018.00580] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022] Open
Abstract
Protein-protein interactions are key factors in executing protein function. These interactions are mediated through different protein domains or modules. An important domain found in many different types of proteins is WW domain. WW domain-containing proteins were shown to be involved in many human diseases including cancer. Some of these proteins function as either tumor suppressor genes or oncogenes, while others show dual identity. Some of these proteins act on their own and alter the function(s) of specific or multiple proteins implicated in cancer, others interact with their partners to compose WW domain modular pathway. In this review, we discuss the role of WW domain-containing proteins in breast tumorigenesis. We give examples of specific WW domain containing proteins that play roles in breast tumorigenesis and explain the mechanisms through which these proteins lead to breast cancer initiation and progression. We discuss also the possibility of using these proteins as biomarkers or therapeutic targets.
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Affiliation(s)
- Abrar Jamous
- Al Quds-Bard College for Arts and Sciences, Al Quds University, Abu Dis, Palestine
| | - Zaidoun Salah
- Al Quds-Bard College for Arts and Sciences, Al Quds University, Abu Dis, Palestine
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Yes-Associated Protein 1 as a Novel Prognostic Biomarker for Gastrointestinal Cancer: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4039173. [PMID: 30539010 PMCID: PMC6261404 DOI: 10.1155/2018/4039173] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/30/2018] [Indexed: 12/13/2022]
Abstract
Background Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which plays a significant role in cell proliferation and tumor progression. The relationship between YAP1 and gastrointestinal cancer has been explored in many previous studies. We conducted a meta-analysis to explore the prognostic effect of YAP1 in patients with gastrointestinal cancer. Methods A systematic search was performed through the PubMed, Web of Science, Embase, and Cochrane library databases to collect eligible studies. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the relationship between YAP1 expression and gastrointestinal cancer clinical outcomes. Results A total of 2941 patients from 18 studies were enrolled. The results showed that elevated YAP1 expression predicted a poor prognosis in gastrointestinal cancer (HR = 1.56; 95% CI: 1.29-1.89; P < 0.001). Subgroup analyses indicated significant association between YAP1 overexpression and shorter OS of patients with esophageal squamous cell carcinoma (HR = 1.85; 95% CI: 1.25-2.73; P = 0.002), gastric cancer (HR = 1.41,95% CI: 1.02-1.95; P = 0.037), and colorectal cancer (pooled HR = 1.75; 95% CI: 1.42-2.15; P < 0.001). However, YAP1 expression did not affect DFS of patients with gastrointestinal cancer (pooled HR = 1.33; 95% CI: 0.95-1.88; P = 0.101). Conclusion Elevated YAP1 expression in patients with gastrointestinal cancer might be related to shorter OS. YAP1 protein could serve as a potential predictor of poor prognosis in gastrointestinal cancer.
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Targeting the Hippo Pathway for Breast Cancer Therapy. Cancers (Basel) 2018; 10:cancers10110422. [PMID: 30400599 PMCID: PMC6266939 DOI: 10.3390/cancers10110422] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 10/31/2018] [Accepted: 11/02/2018] [Indexed: 12/31/2022] Open
Abstract
Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy.
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Abstract
Hippo signaling plays critical roles in regulation of tissue homeostasis, organ size, and tumorigenesis by inhibiting YES-associated protein (YAP) and PDZ-binding protein TAZ through MST1/2 and LATS1/2 pathway. It is also engaged in cross-talk with various other signaling pathways, including WNT, BMPs, Notch, GPCRs, and Hedgehog to further modulate activities of YAP/TAZ. Because YAP and TAZ are transcriptional coactivators that lack DNA-binding activity, both proteins must interact with DNA-binding transcription factors to regulate target gene’s expression. To activate target genes involved in cell proliferation, TEAD family members are major DNA-binding partners of YAP/TAZ. Accordingly, YAP/TAZ were originally classified as oncogenes. However, YAP might also play tumor-suppressing role. For example, YAP can bind to DNA-binding tumor suppressors including RUNXs and p73. Thus, YAP might act either as an oncogene or tumor suppressor depending on its binding partners. Here, we summarize roles of YAP depending on its DNA-binding partners and discuss context-dependent functions of YAP/TAZ.
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Affiliation(s)
- Min-Kyu Kim
- Department of Biochemistry, College of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 28644, Korea
| | - Ju-Won Jang
- Department of Biochemistry, College of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 28644, Korea
| | - Suk-Chul Bae
- Department of Biochemistry, College of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju 28644, Korea
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Dehghanian F, Hojati Z, Hosseinkhan N, Mousavian Z, Masoudi-Nejad A. Reconstruction of the genome-scale co-expression network for the Hippo signaling pathway in colorectal cancer. Comput Biol Med 2018; 99:76-84. [PMID: 29890510 DOI: 10.1016/j.compbiomed.2018.05.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 05/24/2018] [Accepted: 05/24/2018] [Indexed: 01/22/2023]
Abstract
The Hippo signaling pathway (HSP) has been identified as an essential and complex signaling pathway for tumor suppression that coordinates proliferation, differentiation, cell death, cell growth and stemness. In the present study, we conducted a genome-scale co-expression analysis to reconstruct the HSP in colorectal cancer (CRC). Five key modules were detected through network clustering, and a detailed discussion of two modules containing respectively 18 and 13 over and down-regulated members of HSP was provided. Our results suggest new potential regulatory factors in the HSP. The detected modules also suggest novel genes contributing to CRC. Moreover, differential expression analysis confirmed the differential expression pattern of HSP members and new suggested regulatory factors between tumor and normal samples. These findings can further reveal the importance of HSP in CRC.
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Affiliation(s)
- Fariba Dehghanian
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran
| | - Zohreh Hojati
- Division of Genetics, Department of Biology, Faculty of Sciences, University of Isfahan, P.O. Box 81746-73441, Isfahan, Iran.
| | - Nazanin Hosseinkhan
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Zaynab Mousavian
- Department of Computer Science, School of Mathematics, Statistics, and Computer Science, University of Tehran, Tehran, Iran; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
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Zhou Y, Huang T, Zhang J, Cheng ASL, Yu J, Kang W, To KF. Emerging roles of Hippo signaling in inflammation and YAP-driven tumor immunity. Cancer Lett 2018; 426:73-79. [PMID: 29654891 DOI: 10.1016/j.canlet.2018.04.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/04/2018] [Accepted: 04/05/2018] [Indexed: 12/26/2022]
Abstract
Initially identified as a cell and organ size controller, Hippo pathway turns into a hotspot for researchers. Within recent years, more and more mechanisms about Hippo pathway were uncovered. Even though Hippo signaling has been revealed to exert controversial roles according to different cell context and microenvironment, which is because of its diversified interplays with a great variety of signaling transduction cascades; mechanisms other than size-limitation, however, remain to be elucidated. Recently, a growing number of studies tend to put Hippo on inflammatory and immunological focus: its antimicrobial role in flies, its pro- or anti-inflammation in mammals, as well as its relevance to cancerous immunity. From inflammation to tumor immunogenicity, Hippo has been gradually justified to play a crucial role. This review summarized the latest findings regarding the involvement of Hippo pathway in immunity, and a more comprehensive understanding of Hippo pathway will shed light on clinical translational potential even precision medicine.
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Affiliation(s)
- Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Tingting Huang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China
| | - Jinglin Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Alfred S L Cheng
- Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
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Bhaumik P, Ghosh P, Biswas A, Ghosh S, Pal S, Sarkar B, Kumar Dey S. Rare Intronic Variations inTP73Gene Found in Patients with Alzheimer’sDisease. INT J HUM GENET 2018. [DOI: 10.1080/09723757.2017.1421438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Pranami Bhaumik
- Department of Biotechnology, School of Biotechnology and Biological Sciences, Maulana Abul Kalam Azad University of Technology, West Bengal (Formerly known as West Bengal University of Technology) BF – 142, Salt Lake City, Sector I. Kolkata 700 064, West Bengal, India
| | - Priyanka Ghosh
- Department of Biotechnology, School of Biotechnology and Biological Sciences, Maulana Abul Kalam Azad University of Technology, West Bengal (Formerly known as West Bengal University of Technology) BF – 142, Salt Lake City, Sector I. Kolkata 700 064, West Bengal, India
| | - Atanu Biswas
- Department of Neurology, Bangur Institute of Neurosciences, 52/1A, S.N. Pandit Street, Kolkata 700 025, West Bengal, India
| | - Sujay Ghosh
- Department of Zoology, University of Calcutta, (Ballygunge Science College Campus), 35 Ballygunge Circular Road., Kolkata 700 019, West Bengal, India
| | - Sandip Pal
- Department of Neurology, Burdwan Medical College, Burdwan 713 104, West Bengal, India
| | - Biswanath Sarkar
- DNA Laboratory, Anthropological Survey of India, 27 Jawaharlal Nehru Road Kolkata 700 016, West Bengal, India
| | - Subrata Kumar Dey
- Department of Biotechnology, School of Biotechnology and Biological Sciences, Maulana Abul Kalam Azad University of Technology, West Bengal (Formerly known as West Bengal University of Technology) BF – 142, Salt Lake City, Sector I. Kolkata 700 064, West Bengal, India
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MicroRNA-200a confers chemoresistance by antagonizing TP53INP1 and YAP1 in human breast cancer. BMC Cancer 2018; 18:74. [PMID: 29329575 PMCID: PMC5766993 DOI: 10.1186/s12885-017-3930-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 12/18/2017] [Indexed: 01/08/2023] Open
Abstract
Background Emerging evidence suggests molecular and phenotypic association between treatment resistance and epithelial–mesenchymal transition (EMT) in cancer. Compared with the well-defined molecular events of miR-200a in EMT, the role of miR-200a in therapy resistance remains to be elucidated. Methods Breast cancer cells transfected with mimic or inhibitor for miR-200a was assayed for chemoresistance in vitro. miR-200a expression was assessed by quantitative real-time PCR (qRT-PCR) in breast cancer patients treated with preoperative chemotherapy. Luciferase assays, cell proliferation assay were performed to identify the targets of miR-200a and the mechanism by which it promotes treatment resistance. Survival analysis was used to evaluate the prognosis value of miR-200a. Results In this study, our results showed ectopic expression of miR-200a promotes chemoresistance in breast cancer cell lines to several chemotherapeutic agents, whereas inhibition of miR-200a enhances gemcitabine chemosensitivity in resistance cancer cells. We found overexpression of miR-200a was closely associated with poor response to preoperative chemotherapy and poor prognosis in breast cancer patients. Furthermore, knockdown of YAP1 and TP53INP1 phenocopied the effects of miR-200a overexpression, and confirmed that TP53INP1 is a novel target of miR-200a. Remarkably, TP53INP1 expression is inversely correlated with miR-200a expression in Breast cancer cell lines. Taken together, these clinical and experimental results demonstrate that miR-200a is a determinant of chemoresistance of breast cancer. Conclusions Upregulated miR-200a enhances treatment resistance via antagonizing TP53INP1 and YAP1 in breast cancer. Electronic supplementary material The online version of this article (10.1186/s12885-017-3930-0) contains supplementary material, which is available to authorized users.
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Furth N, Aylon Y, Oren M. p53 shades of Hippo. Cell Death Differ 2018; 25:81-92. [PMID: 28984872 PMCID: PMC5729527 DOI: 10.1038/cdd.2017.163] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 08/15/2017] [Accepted: 08/30/2017] [Indexed: 12/11/2022] Open
Abstract
The three p53 family members, p53, p63 and p73, are structurally similar and share many biochemical activities. Yet, along with their common fundamental role in protecting genomic fidelity, each has acquired distinct functions related to diverse cell autonomous and non-autonomous processes. Similar to the p53 family, the Hippo signaling pathway impacts a multitude of cellular processes, spanning from cell cycle and metabolism to development and tumor suppression. The core Hippo module consists of the tumor-suppressive MST-LATS kinases and oncogenic transcriptional co-effectors YAP and TAZ. A wealth of accumulated data suggests a complex and delicate regulatory network connecting the p53 and Hippo pathways, in a highly context-specific manner. This generates multiple layers of interaction, ranging from interdependent and collaborative signaling to apparent antagonistic activity. Furthermore, genetic and epigenetic alterations can disrupt this homeostatic network, paving the way to genomic instability and cancer. This strengthens the need to better understand the nuances that control the molecular function of each component and the cross-talk between the different components. Here, we review interactions between the p53 and Hippo pathways within a subset of physiological contexts, focusing on normal stem cells and development, as well as regulation of apoptosis, senescence and metabolism in transformed cells.
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Affiliation(s)
- Noa Furth
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Yael Aylon
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
- Department of Molecular Cell Biology, The Weizmann Institute, POB 26, 234 Herzl Street, Rehovot 7610001, Israel. Tel: +972 89342358; Fax: +972 89346004; E-mail: or
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
- Department of Molecular Cell Biology, The Weizmann Institute, POB 26, 234 Herzl Street, Rehovot 7610001, Israel. Tel: +972 89342358; Fax: +972 89346004; E-mail: or
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