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Nutsch K, Trujillo MN, Song L, Erb MA, Chen JJ, Galligan JJ, Bollong MJ. Augmented Acyl-CoA Biosynthesis Promotes Resistance to TEAD Palmitoylation Site Inhibition. ACS Chem Biol 2025; 20:967-975. [PMID: 40179049 DOI: 10.1021/acschembio.5c00162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Activation of the YAP-TEAD transcriptional complex drives the growth of several cancer types and is a key resistance mechanism to targeted therapies. Accordingly, a host of pharmacological inhibitors to TEAD family paralogs have been developed, yet little is known as to the resistance mechanisms that might arise against this emerging therapeutic class. Here, we report that genetic augmentation of de novo coenzyme A biosynthesis desensitizes YAP-dependent cancer cells to treatment with TEAD inhibitors, an effect driven by increased levels of palmitoyl-CoA that outcompete drug for engagement of the lipid-binding pocket. This work uncovers a potential therapeutic resistance mechanism to TEAD palmitoylation site inhibition with implications for future combinatorial treatments in the clinic.
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Affiliation(s)
- Kayla Nutsch
- Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037-1000, United States
| | - Marissa N Trujillo
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721-0202, United States
| | - Lirui Song
- A Division of Scripps Research, Calibr-Skaggs Institute for Innovative Medicines, La Jolla, California 92037-1000, United States
| | - Michael A Erb
- Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037-1000, United States
| | - Jian Jeffery Chen
- A Division of Scripps Research, Calibr-Skaggs Institute for Innovative Medicines, La Jolla, California 92037-1000, United States
| | - James J Galligan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721-0202, United States
| | - Michael J Bollong
- Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037-1000, United States
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Fan L, Guo X, Washington MK, Shi J, Ness RM, Liu Q, Wen W, Huang S, Liu X, Cai Q, Zheng W, Coffey RJ, Shrubsole MJ, Su T. Yes-associated protein plays oncogenic roles in human sporadic colorectal adenomas. Carcinogenesis 2025; 46:bgaf007. [PMID: 39977302 PMCID: PMC11923420 DOI: 10.1093/carcin/bgaf007] [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: 09/06/2024] [Revised: 02/04/2025] [Accepted: 02/18/2025] [Indexed: 02/22/2025] Open
Abstract
The role of Hippo-Yes-associated protein (YAP) in human colorectal cancer (CRC) presents contradictory results. We examined the function of YAP in the early stages of CRC by quantitatively measuring the expression of phospho-YAPS127 (p-YAP) and five APC-related proteins in 145 sporadic adenomas from the Tennessee Colorectal Polyp Study, conducting APC sequencing for 114 adenomas, and analyzing YAP-correlated cancer pathways using gene expression data from 326 adenomas obtained from Gene Expression Omnibus. The p-YAP expression was significantly correlated with YAP expression (r = 0.53, P < .0001) and nuclear β-catenin (r = 0.26, P = .0018) in adenoma tissues. Both p-YAP and nuclear β-catenin were associated with APC mutations (P = .05). A strong association was observed between p-YAP overexpression and advanced adenoma odds (OR = 12.62, 95% CI = 4.57-34.86, P trend < .001), which persisted after adjusting for covariates and biomarkers (OR = 12.31, 95% CI = 3.78-40.10, P trend < .0001). P-YAP exhibited a sensitivity of 77.4% and specificity of 78.2% in defining advanced versus nonadvanced adenomas. Additionally, synergistic interaction was noted between p-YAP positivity and nuclear β-catenin on advanced adenomas (OR = 16.82, 95% CI = 4.41-64.08, P < .0001). YAP-correlated genes were significantly enriched in autophagy, unfolded protein response, and sirtuin pathways showing predominantly pro-tumorigenic alterations. Collectively, YAP plays an oncogenic role in interacting with Wnt as well as other cancer pathways within human sporadic adenomas. P-YAP could be a potential biomarker for human high-risk sporadic adenomas.
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Affiliation(s)
- Lei Fan
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
| | - Xingyi Guo
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Mary K Washington
- Department of Pathology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Jiajun Shi
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Reid M Ness
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Qi Liu
- Center for Quantitative Sciences and Department of Biostatistics, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Shuya Huang
- Department of Breast Surgery, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, Shandong 250031, China
| | - Xiao Liu
- Center for Quantitative Sciences and Department of Biostatistics, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Robert J Coffey
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States
- Cell and Development Biology, Vanderbilt University, 1211 Medical Center Drive, Nashville, TN 37232, United States
| | - Martha J Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
| | - Timothy Su
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2525 West End Avenue, Nashville, TN 37203, United States
- GRECC, Department of Veterans Affairs, Tennessee Valley Healthcare System, 1310 24th Avenue S., Nashville, TN 37212, United States
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Han J, Kim S, Hwang YH, Kim SA, Lee Y, Kim J, Cho S, Woo J, Jeong C, Kwon M, Nam G, Kim I. Novel Personalized Cancer Vaccine Using Tumor Extracellular Vesicles with Attenuated Tumorigenicity and Enhanced Immunogenicity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308662. [PMID: 38666427 PMCID: PMC11220679 DOI: 10.1002/advs.202308662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 04/08/2024] [Indexed: 07/04/2024]
Abstract
Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor-specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use. This study introduces a novel approach to repurpose TEVs as potent personalized cancer vaccines. The study shows that inhibition of both YAP and autophagy not only diminishes the malignancy-associated traits of TEVs but also enhances their immunogenic attributes by enriching their load of tumor antigens and adjuvants. These revamped TEVs, termed attenuated yet immunogenically potentiated TEVs (AI-TEVs), showcase potential in inhibiting tumor growth, both as a preventive measure and a possible treatment for recurrent cancers. They prompt a tumor-specific and enduring immune memory. In addition, by showing that AI-TEVs can counteract cancer growth in a personalized vaccine approach, a potential strategy is presented for developing postoperative cancer immunotherapy that's enduring and tailored to individual patients.
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Affiliation(s)
- Jihoon Han
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Seohyun Kim
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- Department of Research and DevelopmentShiftBioSeoul02751Republic of Korea
| | - Yeong Ha Hwang
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Seong A Kim
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Yeji Lee
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Jihong Kim
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Seongeon Cho
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Jiwan Woo
- Research Animal Resource CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
| | - Cherlhyun Jeong
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
- KHU‐KIST Department of Converging Science and TechnologyKyung Hee UniversitySeoul02447Republic of Korea
| | - Minsu Kwon
- Department of OtolaryngologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoul05505Republic of Korea
| | - Gi‐Hoon Nam
- Department of Research and DevelopmentShiftBioSeoul02751Republic of Korea
- Department of Biochemistry and Molecular BiologyKorea University College of MedicineSeoul02841Republic of Korea
| | - In‐San Kim
- KU‐KIST Graduate School of Converging Science and TechnologyKorea UniversitySeoul02841Republic of Korea
- Chemical and Biomedical Integrative Research CenterKorea Institute of Science and Technology (KIST)Seoul02792Republic of Korea
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Seidelin JB, Bronze M, Poulsen A, Attauabi M, Woetmann A, Mead BE, Karp JM, Riis LB, Bjerrum JT. Non-TGFβ profibrotic signaling in ulcerative colitis after in vivo experimental intestinal injury in humans. Am J Physiol Gastrointest Liver Physiol 2024; 327:G70-G79. [PMID: 38713614 DOI: 10.1152/ajpgi.00074.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/09/2024]
Abstract
Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high-resolution endoscopic imaging, histological assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 patients with UC in remission and 20 control subjects. Human ER had a 48-h lag before induction of regenerative epithelial cells [wound-associated epithelial (WAE) and transit amplifying (TA) cells] along with the increase of fibroblast-derived stem cell growth factor gremlin 1 mRNA (GREM1). However, UC deconvolution data showed rapid induction of inflammatory fibroblasts and upregulation of major structural ECM collagen mRNAs along with tissue inhibitor of metalloproteinase 1 (TIMP1), suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor β (TGFβ) mRNA, whereas the profibrotic cytokines interleukin 13 (IL13) and IL11 were upregulated in UC, suggesting that human postinjury responses could be TGFβ-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end-organ failure, i.e., intestinal damage.NEW & NOTEWORTHY The study reveals the regulatory dynamics of epithelial regeneration and extracellular matrix remodeling after experimental injury of the human colon in vivo and shows that human intestinal regeneration is different from data obtained from animals. A lag phase in epithelial restitution is associated with induction of stromal cell-derived epithelial growth factors. Postinjury regeneration is transforming growth factor β-independent, and we find a profibrotic response in patients with ulcerative colitis despite being in remission.
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Affiliation(s)
- Jakob B Seidelin
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mariana Bronze
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Anja Poulsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mohamed Attauabi
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anders Woetmann
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
| | - Benjamin E Mead
- Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Koch Institute for Integrative Cancer Research; Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Harvard Stem Cell Institute, Cambridge, Massachusetts, United States
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Department of Chemistry; Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, United States
| | - Jeffrey M Karp
- Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
- Harvard Stem Cell Institute, Cambridge, Massachusetts, United States
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, United States
- Harvard Medical School, Boston, Massachusetts, United States
- Department of Anesthesiology, Perioperative and Pain Medicine,Brigham and Women's Hospital, Cambridge, Massachusetts, United States
| | - Lene B Riis
- Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Jacob T Bjerrum
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
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Powała K, Żołek T, Brown G, Kutner A. Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ. Int J Mol Sci 2024; 25:6568. [PMID: 38928275 PMCID: PMC11203493 DOI: 10.3390/ijms25126568] [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: 05/21/2024] [Revised: 06/06/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
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Affiliation(s)
- Katarzyna Powała
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland
| | - Teresa Żołek
- Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland
| | - Geoffrey Brown
- School of Biomedical Sciences, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK;
| | - Andrzej Kutner
- Department of Drug Chemistry Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland;
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Naser AN, Xing T, Tatum R, Lu Q, Boyer PJ, Chen YH. Colonic crypt stem cell functions are controlled by tight junction protein claudin-7 through Notch/Hippo signaling. Ann N Y Acad Sci 2024; 1535:92-108. [PMID: 38598500 PMCID: PMC11111361 DOI: 10.1111/nyas.15137] [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: 07/13/2023] [Revised: 02/26/2024] [Accepted: 03/13/2024] [Indexed: 04/12/2024]
Abstract
The tight junction protein claudin-7 is essential for tight junction function and intestinal homeostasis. Cldn7 deletion in mice leads to an inflammatory bowel disease-like phenotype exhibiting severe intestinal epithelial damage, weight loss, inflammation, mucosal ulcerations, and epithelial hyperplasia. Claudin-7 has also been shown to be involved in cancer metastasis and invasion. Here, we test our hypothesis that claudin-7 plays an important role in regulating colonic intestinal stem cell function. Conditional knockout of Cldn7 in the colon led to impaired epithelial cell differentiation, hyperproliferative epithelium, a decrease in active stem cells, and dramatically altered gene expression profiles. In 3D colonoid culture, claudin-7-deficient crypts were unable to survive and form spheroids, emphasizing the importance of claudin-7 in stem cell survival. Inhibition of the Hippo pathway or activation of Notch signaling partially rescued the defective stem cell behavior. Concurrent Notch activation and Hippo inhibition resulted in restored colonoid survival, growth, and differentiation to the level comparable to those of wild-type derived crypts. In this study, we highlight the essential role of claudin-7 in regulating Notch and Hippo signaling-dependent colonic stem cell functions, including survival, self-renewal, and differentiation. These new findings may shed light on potential avenues to explore for drug development in colorectal cancer.
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Affiliation(s)
- Amna N. Naser
- Department of Anatomy and Cell Biology, University of South Carolina, Columbia, South Carolina, USA
| | - Tiaosi Xing
- Department of Anatomy and Cell Biology, University of South Carolina, Columbia, South Carolina, USA
- Neural and Behavioral Science Department, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Rodney Tatum
- Department of Anatomy and Cell Biology, University of South Carolina, Columbia, South Carolina, USA
| | - Qun Lu
- Department of Anatomy and Cell Biology, University of South Carolina, Columbia, South Carolina, USA
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA
| | - Philip J. Boyer
- Department of Pathology and Laboratory Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Yan-Hua Chen
- Department of Anatomy and Cell Biology, University of South Carolina, Columbia, South Carolina, USA
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina, USA
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Kumar A, BharathwajChetty B, Manickasamy MK, Unnikrishnan J, Alqahtani MS, Abbas M, Almubarak HA, Sethi G, Kunnumakkara AB. Natural compounds targeting YAP/TAZ axis in cancer: Current state of art and challenges. Pharmacol Res 2024; 203:107167. [PMID: 38599470 DOI: 10.1016/j.phrs.2024.107167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/12/2024]
Abstract
Cancer has become a burgeoning global healthcare concern marked by its exponential growth and significant economic ramifications. Though advancements in the treatment modalities have increased the overall survival and quality of life, there are no definite treatments for the advanced stages of this malady. Hence, understanding the diseases etiologies and the underlying molecular complexities, will usher in the development of innovative therapeutics. Recently, YAP/TAZ transcriptional regulation has been of immense interest due to their role in development, tissue homeostasis and oncogenic transformations. YAP/TAZ axis functions as coactivators within the Hippo signaling cascade, exerting pivotal influence on processes such as proliferation, regeneration, development, and tissue renewal. In cancer, YAP is overexpressed in multiple tumor types and is associated with cancer stem cell attributes, chemoresistance, and metastasis. Activation of YAP/TAZ mirrors the cellular "social" behavior, encompassing factors such as cell adhesion and the mechanical signals transmitted to the cell from tissue structure and the surrounding extracellular matrix. Therefore, it presents a significant vulnerability in the clogs of tumors that could provide a wide window of therapeutic effectiveness. Natural compounds have been utilized extensively as successful interventions in the management of diverse chronic illnesses, including cancer. Owing to their capacity to influence multiple genes and pathways, natural compounds exhibit significant potential either as adjuvant therapy or in combination with conventional treatment options. In this review, we delineate the signaling nexus of YAP/TAZ axis, and present natural compounds as an alternate strategy to target cancer.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Jyothsna Unnikrishnan
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia; BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
| | - Hassan Ali Almubarak
- Division of Radiology, Department of Medicine, College of Medicine and Surgery, King Khalid University, Abha 61421, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 117699, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam 781039, India.
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8
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Li J, Zhang X, Liu Y, Zhou J, Shen L, Yue G. Expressions and Clinical Significance of Met and YAP in Gastric Cancer Tissue Microarray. Gastroenterol Res Pract 2024; 2024:5591298. [PMID: 38634107 PMCID: PMC11022516 DOI: 10.1155/2024/5591298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 03/14/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024] Open
Abstract
Objective This study is aimed at investigating the expression of Met and YAP in gastric cancer and their impact on clinical prognosis. Methods Tissue samples and clinical data were collected from 89 patients with gastric cancer. Immunohistochemistry was performed to quantify the expression of Met and YAP using tissue microarray. The correlation between the expressions of Met, YAP, and clinicopathological characteristics of patients was determined using a chi-square test. Survival analysis was conducted using the Kaplan-Meier method, while multivariate survival analysis was performed using the Cox proportional hazard model. Bioinformatics analysis was carried out by downloading chip data from TCGA. Results The expression levels of both Met and YAP were significantly higher in gastric cancer tissues compared to adjacent tissues (P < 0.001). Met expression showed a positive association with P53 and CD133, whereas YAP expression correlated positively with tumor grade and CD133 (P < 0.05). Pearson's analysis revealed a significant correlation between Met expression and VEGFR as well as CD133, while YAP expression correlated with Ki67 and VEGFR (P < 0.05). Patients with high levels of both Met and YAP exhibited decreased survival time (P < 0.01). Furthermore, Met expression, N stage, and VEGFR were identified as independent risk factors for gastric cancer prognosis (P < 0.05), whereas no such association was observed for YAP expression. Bioinformatics analysis demonstrated a significant correlation between the expressions of Met and YAP; both proteins were highly expressed in gastric cancer patients accompanied by markedly reduced survival time. Conclusion The expressions of Met and YAP are closely associated with the survival outcomes as well as clinicopathological features in patients with gastric cancer. Moreover, our findings highlight that Met serves as an independent prognostic factor for gastric cancer.
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Affiliation(s)
- Jinxia Li
- Hunan University of Chinese Medicine, Changsha 410208, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xinyun Zhang
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Ying Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jinyong Zhou
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Li Shen
- Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Guangxin Yue
- Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China
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9
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [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: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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10
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Jiang Y, Fu L, Liu B, Li F. YAP induces FAK phosphorylation to inhibit gastric cancer cell proliferation via upregulation of HMGB1. Int J Biol Macromol 2024; 262:130037. [PMID: 38331059 DOI: 10.1016/j.ijbiomac.2024.130037] [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: 11/20/2023] [Revised: 01/29/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
Yes associated protein (YAP) is the main effector protein in the Hippo pathway, regulating cell growth by binding to transcription factors in the nucleus. However, the mechanisms by which YAP regulates the development and progression of gastric cancer (GC) remain largely unknown. In this study, bioinformatics analysis determined that YAP was significantly upregulated in GC and associated with poor prognosis. In addition, YAP deletion inhibits proliferation and migration of GC cells in vitro, while overexpression of YAP has the opposite effect. Mechanistically, overexpression of YAP induced FAK phosphorylation in gastric cancer cells, whereas knockdown of YAP had the opposite effect. Importantly, translocation expressed mutant plasmid YAP-S94A (YAP1 mutant without TEAD binding site) did not significantly change the level of FAK phosphorylation. Furthermore, Verteporfin (a small molecule inhibitor of YAP) interrupted the YAP-TEAD interaction and inhibited FAK phosphorylation, confirming that YAP can induce FAK phosphorylation in a TEAD-dependent manner. In addition, the silencing of FAK or the use of FAK inhibitors inhibited the aggregation of YAP proteins in the nucleus, forming a FAK-YAP positive feedback loop. Finally, we identify the FAK upstream gene, HMGB1, as a direct transcriptional target of YAP-TEAD. Silencing HMGB1 reversed YAP-induced FAK activation as well as cell proliferation and migration. Collectively, our results reveal a new signalling axis, YAP/HMGB1/FAK, in the regulation of cell proliferation and migration, and provide new insights into the crosstalk between Hippo signalling and cell proliferation.
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Affiliation(s)
- Yunhe Jiang
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese, Ministry of Education, College of Basic Medicine, Jilin University, Changchun, China
| | - Lifu Fu
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese, Ministry of Education, College of Basic Medicine, Jilin University, Changchun, China
| | - Bin Liu
- Cardiovascular Disease Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Fan Li
- Department of Pathogenobiology, The Key Laboratory of Zoonosis, Chinese, Ministry of Education, College of Basic Medicine, Jilin University, Changchun, China; The Key Laboratory for Bionics Engineering, Ministry of Education, Jilin University, Changchun, China; Engineering Research Center for Medical Biomaterials of Jilin Province, Jilin University, Changchun, China; Key Laboratory for Health Biomedical Materials of Jilin Province, Jilin University, Changchun, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang, China.
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11
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Tai Y, Shang J. Wnt/β-catenin signaling pathway in the tumor progression of adrenocortical carcinoma. Front Endocrinol (Lausanne) 2024; 14:1260701. [PMID: 38269250 PMCID: PMC10806569 DOI: 10.3389/fendo.2023.1260701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 12/20/2023] [Indexed: 01/26/2024] Open
Abstract
Adrenocortical carcinoma (ACC) is an uncommon, aggressive endocrine malignancy with a high rate of recurrence, a poor prognosis, and a propensity for metastasis. Currently, only mitotane has received certification from both the US Food and Drug Administration (FDA) and the European Medicines Agency for the therapy of advanced ACC. However, treatment in the advanced periods of the disorders is ineffective and has serious adverse consequences. Completely surgical excision is the only cure but has failed to effectively improve the survival of advanced patients. The aberrantly activated Wnt/β-catenin pathway is one of the catalysts for adrenocortical carcinogenesis. Research has concentrated on identifying methods that can prevent the stimulation of the Wnt/β-catenin pathway and are safe and advantageous for patients in view of the absence of effective treatments and the frequent alteration of the Wnt/β-catenin pathway in ACC. Comprehending the complex connection between the development of ACC and Wnt/β-catenin signaling is essential for accurate pharmacological targets. In this review, we summarize the potential targets between adrenocortical carcinoma and the Wnt/β-catenin signaling pathway. We analyze the relevant targets of drugs or inhibitors that act on the Wnt pathway. Finally, we provide new insights into how drugs or inhibitors may improve the treatment of ACC.
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Affiliation(s)
- Yanghao Tai
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
| | - Jiwen Shang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences Tongji Shanxi Hospital, Taiyuan, China
- Department of Ambulatory Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
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12
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Salla M, Guo J, Joshi H, Gordon M, Dooky H, Lai J, Capicio S, Armstrong H, Valcheva R, Dyck JRB, Thiesen A, Wine E, Dieleman LA, Baksh S. Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation. Int J Mol Sci 2023; 24:ijms24065967. [PMID: 36983040 PMCID: PMC10055751 DOI: 10.3390/ijms24065967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/29/2023] Open
Abstract
Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.
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13
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Chen Y, Wang Y, Zhai Y, Yuan Y, Wang J, Jin Y, Dang L, Song L, Chen C, Wang Y. Cinobufacini injection suppresses the proliferation of human osteosarcoma cells by inhibiting PIN1-YAP/TAZ signaling pathway. Front Pharmacol 2023; 14:1081363. [PMID: 37006999 PMCID: PMC10063998 DOI: 10.3389/fphar.2023.1081363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/08/2023] [Indexed: 03/19/2023] Open
Abstract
Cinobufacini injection (CI), an aqueous extract of Cutis Bufonis, is clinically used for cancer therapy in China, but its molecular mechanism for the treatment of osteosarcoma (OS) remains unclear. We constructed U2OS ectopic subcutaneous tumor model to verify the anti-OS effect of CI in vivo. Meanwhile, cell proliferation of U2OS and MG63 cells was monitored in vitro using the CCK-8 assay, colony formation and morphological changes. Cell cycle arrest and apoptosis were detected by flow cytometry and western blot, which showed that CI significantly inhibited proliferation, induced cell cycle arrest and apoptosis in human OS cells. The further RNA-seq results identified that the Hippo signaling pathway was involved in the anti-OS effect of CI. YAP/TAZ are two major components of the Hippo pathway in breast cancer and are positively regulated by prolyl isomerase PIN1, we assessed their role in OS using both clinicopathological sections and western blots. CI also inhibited PIN1 enzyme activity in a dose-dependent manner, which resulted in impaired PIN1, YAP, and TAZ expression in vitro and in vivo. Additionally, 15 potential compounds of CI were found to occupy the PIN1 kinase domain and inhibit its activity. In summary, CI plays an anti-OS role by down-regulating the PIN1-YAP/TAZ pathway.
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Affiliation(s)
- Yuru Chen
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, China
| | - Yanyan Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yu Zhai
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ye Yuan
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, China
| | - Junhong Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yajing Jin
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, China
| | - Lingling Dang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, China
| | - Liming Song
- Department of Joint Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Changbao Chen
- Department of Spinal Surgery, Tianjin Hospital, Tianjin University, Tianjin, China
| | - Yu Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin, China
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14
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Naktubtim C, Payuhakrit W, Uttarawichien T, Hassametto A, Suwannalert P. YAP, a novel target regulates F-actin rearrangement-associated CAFs transformation and promotes colorectal cancer cell progression. Biomed Pharmacother 2022; 155:113757. [DOI: 10.1016/j.biopha.2022.113757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/16/2022] [Accepted: 09/26/2022] [Indexed: 11/02/2022] Open
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15
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Targeting the Hippo Pathway in Gastric Cancer and Other Malignancies in the Digestive System: From Bench to Bedside. Biomedicines 2022; 10:biomedicines10102512. [PMID: 36289774 PMCID: PMC9599207 DOI: 10.3390/biomedicines10102512] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Abstract
The Hippo pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration under physiological conditions, and its aberrations have been well studied to promote tumor initiation and progression. Dysregulation of the Hippo tumor suppressor signaling frequently occurs in gastric cancer (GC) and other solid tumors and contributes to cancer development through modulating multiple aspects, including cell proliferation, survival, metastasis, and oncotherapy resistance. In the clinic, Hippo components also possess diagnostic and prognostic values for cancer patients. Considering its crucial role in driving tumorigenesis, targeting the Hippo pathway may greatly benefit developing novel cancer therapies. This review summarizes the current research progress regarding the core components and regulation of the Hippo pathway, as well as the mechanism and functional roles of their dysregulation in gastrointestinal malignancies, especially in GC, and discusses the therapeutic potential of targeting the Hippo pathway against cancers.
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16
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Lu S, Jiang M, Chen Q, Luo X, Cao Z, Huang H, Zheng M, Du J. Upregulated YAP promotes oncogenic CTNNB1 expression contributing to molecular pathology of hepatoblastoma. Pediatr Blood Cancer 2022; 69:e29705. [PMID: 35404538 DOI: 10.1002/pbc.29705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Hepatoblastoma (HB) is one of the most common cancers in children. Recent studies have shown that the occurrence of nuclear accumulation of β-catenin reaches 90%-100% because of the anomalous activation of the Wnt pathway in HB patients. Furthermore, emerging studies have shown that concomitant activated forms of YAP and β-catenin trigger the formation and progression of HB. YAP might play a vital role in β-catenin-mediated HB development. However, the molecular mechanisms by which YAP/TEAD4 transcription factor regulates CTNNB1 underlying HB pathogenesis are still unclear. PROCEDURE YAP and CTNNB1 expression and correlation were analyzed by a combination of network enrichment analysis and gene set enrichment analysis of the public microarray datasets (GSE131329 and GSE81928). The protein levels of YAP and β-catenin were further validated by Western blotting in paired patients' samples. The direct interplay between YAP/TEAD4 and the promoter region of CTNNB1 was proven by the combination of dual-luciferase report assay and chromatin immunoprecipitation assay. RESULTS YAP-conserved signature and WNT signaling pathway were significantly enriched in HB patients, with upregulated expression of YAP and β-catenin compared to non-HB patients. Further functional assays demonstrated that YAP/TEAD4 transcription factor complex could bind to the CTNNB1 promoter region directly to promote β-catenin expression and cell proliferation. Targeting the YAP/TEAD4 complex with a specific small-molecule compound markedly suppressed HepaG2 cell proliferation. CONCLUSIONS As the upstream transcription factor of CTNNB1, YAP/TEAD4 is a promising target for the treatment of HB patients with high levels of YAP and β-catenin.
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Affiliation(s)
- Songxian Lu
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Min Jiang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qi Chen
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xufeng Luo
- Institute for Lymphoma Research, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Zhenjie Cao
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Huang
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mingjun Zheng
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junpeng Du
- Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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17
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Wang X, Zhou Y, Wang Y, Wang X, Zhang Y, Mao Y, Zhang L, Qi J, Zhang Y, Lyu F, Gu L, Yu R, Zhou X. SU4312 Represses Glioma Progression by Inhibiting YAP and Inducing Sensitization to the Effect of Temozolomide. J Clin Med 2022; 11:jcm11164765. [PMID: 36013004 PMCID: PMC9410026 DOI: 10.3390/jcm11164765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 07/31/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain–blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment.
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Affiliation(s)
- Xu Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Yi Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Yan Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China
| | - Xiang Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Yu Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China
| | - Yufei Mao
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Long Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Ji Qi
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Yining Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Feng Lyu
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Linbo Gu
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221004, China
| | - Rutong Yu
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China
- Correspondence: (R.Y.); (X.Z.)
| | - Xiuping Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China
- Correspondence: (R.Y.); (X.Z.)
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18
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MALAT1 in colorectal cancer: Its implication as a diagnostic, prognostic, and predictive biomarker. Gene 2022; 843:146791. [PMID: 35961438 DOI: 10.1016/j.gene.2022.146791] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/26/2022] [Accepted: 08/05/2022] [Indexed: 12/13/2022]
Abstract
Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), originally described as a prognostic biomarker remarkably linked with metastasis potential in lung cancer, has been identified as contributing to many diseases, including colorectal cancer (CRC). This long non-coding RNA (lncRNA) has come to the forefront of lncRNA research for its implications in cancer-related processes, such as cell proliferation and migration. In general, lncRNAs are recognized as enhancers, scaffolds, or decoys for a variety of oncogenes and tumor suppressors, although our understanding of lncRNA functions and mechanisms of action is still limited. Nowadays, cancer research is attracted to lncRNAs' ability to improve the early diagnosis of cancer, determine patients' prognosis, or predict therapy outcomes. In this review, we aimed to evaluate recent publications trying to uncover the cellular mechanisms of MALAT1-mediated regulation, and its potential exploitation in the management of CRC. The conclusions of this review provide robust support for the essential role of MALAT1 in CRC development and future personalized therapy.
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19
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Mia MM, Singh MK. Emerging roles of the Hippo signaling pathway in modulating immune response and inflammation-driven tissue repair and remodeling. FEBS J 2022; 289:4061-4081. [PMID: 35363945 DOI: 10.1111/febs.16449] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/17/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023]
Abstract
Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, and differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury- and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.
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Affiliation(s)
- Masum M Mia
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore
| | - Manvendra K Singh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
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20
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Zhang Y, Wang X, Zhou X. Functions of Yes-association protein (YAP) in cancer progression and anticancer therapy resistance. BRAIN SCIENCE ADVANCES 2022. [DOI: 10.26599/bsa.2022.9050008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The Hippo pathway, a highly conserved kinase cascade, regulates cell proliferation, apoptosis, organ size, and tissue homeostasis. Dysregulation of this pathway reportedly plays an important role in the progression of various human cancers. Yes-association protein (YAP), the Hippo pathway’s core effector, is considered a marker for cancer therapy and patient prognosis. In addition, studies have indicated that YAP is involved in promoting anticancer drug resistance. This review summarizes current knowledge on YAP’s role in cancer progression, anticancer drug resistance, and advances in the development of YAP-targeting drugs. A thorough understanding of the complex interactions among molecular, cellular, and environmental factors concerning YAP function in cancer progression may provide new insight into the underlying mechanism of anticancer drug resistance. It might lead to improved prognosis through novel combined therapies.
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Affiliation(s)
- Yu Zhang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiang Wang
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- The Graduate School, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- These authors contributed equally to this work
| | - Xiuping Zhou
- Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
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21
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Feng P, Zhang J, Zhang J, Liu X, Pan L, Chen D, Ji M, Lu F, Li P, Li G, Sun T, Li J, Ye J, Ji C. Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD+ AML Cells. Front Cell Dev Biol 2022; 10:842214. [PMID: 35656547 PMCID: PMC9152322 DOI: 10.3389/fcell.2022.842214] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/18/2022] [Indexed: 12/19/2022] Open
Abstract
The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cell resistance to chemo- and targeted therapy. Mass spectrometric assay revealed that DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown was partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage, and significantly attenuated FLT3-ITD+ AML cell resistance. In addition, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+ AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients.
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Affiliation(s)
- Panpan Feng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingru Zhang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Juan Zhang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaomin Liu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lina Pan
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Dawei Chen
- Laboratory of Medical Chemistry, GIGA-Stem Cells, Faculty of Medicine, University of Liege, CHU, Liege, Belgium
| | - Min Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fei Lu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Peng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tao Sun
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingxin Li
- Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingjing Ye
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Chunyan Ji, ; Jingjing Ye,
| | - Chunyan Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- *Correspondence: Chunyan Ji, ; Jingjing Ye,
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22
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Liu P, Zeng J, Yang G. Expression of yes‑associated protein, β‑catenin and smoothened, and their clinical significance in invasive breast cancer. Exp Ther Med 2022; 23:429. [PMID: 35607374 PMCID: PMC9121206 DOI: 10.3892/etm.2022.11356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/22/2022] [Indexed: 12/05/2022] Open
Abstract
The expression profile and role of yes-associated protein (YAP) in occurrence and development of breast cancer is ambiguous. The present study aimed to explore the relationship among the YAP, β-catenin and smoothened (SMO) signaling pathways to provide a theoretical basis for the clinical diagnosis and treatment of invasive breast cancer. Immunohistochemistry was used to determine the protein expression levels of YAP, β-catenin and SMO in tumor, tumor-adjacent and normal breast tissue. The possible association between the expression levels of these three proteins and the clinicopathological features of patients with breast cancer was then analyzed by the χ2 test. The protein expression of YAP was found to be downregulated, whilst β-catenin and SMO expression were found to be upregulated in tumor tissues as compared with that in normal breast tissues. In addition, the expression of YAP in breast cancer tissues was found to be associated with that of human epidermal growth factor receptor 2 (HER2), progesterone and estrogen receptors. By contrast, the protein expression of β-catenin and SMO in breast cancer tissues was only associated with HER2. There was a negative correlation between the expression of YAP and SMO protein in breast cancer tissues. Compared with that in the changes in each of YAP, β-catenin and SMO protein expression levels individually, their combined changes in expression were demonstrated to associate significantly with the tumor histological grade. To conclude, data from the present study suggest that the combined protein expression of YAP, β-catenin and SMO can be used as a prognostic indicator for the treatment of invasive breast cancer.
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Affiliation(s)
- Pengju Liu
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Jianfeng Zeng
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Gaohua Yang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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23
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Knockdown of YAP/TAZ sensitizes tamoxifen-resistant MCF7 breast cancer cells. Biochem Biophys Res Commun 2022; 601:73-78. [PMID: 35231654 DOI: 10.1016/j.bbrc.2022.02.083] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 11/24/2022]
Abstract
Although endocrine therapy with tamoxifen has improved survival in breast cancer patients, resistance to this therapy remains one of the major causes of breast cancer mortality. In the present study, we found that the expression level of YAP/TAZ in tamoxifen-resistant MCF7 (MCF7-TR) breast cancer cells was significantly increased compared with that in MCF7 cells. Knockdown of YAP/TAZ with siRNA sensitized MCF7-TR cells to tamoxifen. Furthermore, siRNA targeting PSAT1, a downstream effector of YAP/TAZ, enhanced sensitivity to tamoxifen in MCF7-TR cells. Additionally, mTORC1 activity and survivin expression were significantly decreased during cell death induced by combination treatment with YAP/TAZ or PSAT1 siRNA and tamoxifen. In conclusion, targeting the YAP/TAZ-PSAT1 axis could sensitize tamoxifen-resistant MCF7 breast cancer cells by modulating the mTORC1-survivin axis.
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24
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A Critical YAP in Malignancy of HCC Is Regulated by Evodiamine. Int J Mol Sci 2022; 23:ijms23031855. [PMID: 35163776 PMCID: PMC8837083 DOI: 10.3390/ijms23031855] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/20/2022] [Accepted: 01/27/2022] [Indexed: 12/18/2022] Open
Abstract
Liver cancer has relatively few early symptoms and is usually diagnosed in the advanced stage. Sorafenib is the only first-line anticancer drug approved by the Food and Drug Administration (FDA) for advanced HCC; however, its use is limited due to resistance. Therefore, the development of new drugs is essential to achieving customized treatment. Many studies have suggested that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) is associated with metastasis and cancer formation and progression in various cancers. In the present study, YAP was overexpressed in various patient-derived hepatocarcinoma (HCC) tissues. In addition, this study examined whether evodiamine (which has anticancer effects) can inhibit YAP and, if so, modulate HCC. Evodiamine significantly reduced both the YAP level and cell growth of HCC in a dose-dependent manner. Biochemical analysis indicated mitochondria dysfunction-mediated apoptosis to be the cause of the reduction in HCC cell growth by evodiamine. YAP was overexpressed in metastatic HCC tissues as well when compared to primary HCC tissues. Migration and invasion analysis showed that evodiamine has anti-metastatic ability on Hep3B and Huh-7 cells and reduces the level of vimentin, an EMT marker. In conclusion, YAP is a critical target in HCC therapy, and evodiamine can be an effective HCC anticancer drug by reducing the YAP level.
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25
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Kim M, Ly SH, Xie Y, Duronio GN, Ford-Roshon D, Hwang JH, Sulahian R, Rennhack JP, So J, Gjoerup O, Talamas JA, Grandclaudon M, Long HW, Doench JG, Sethi NS, Giannakis M, Hahn WC. YAP1 and PRDM14 converge to promote cell survival and tumorigenesis. Dev Cell 2022; 57:212-227.e8. [PMID: 34990589 PMCID: PMC8827663 DOI: 10.1016/j.devcel.2021.12.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/15/2021] [Accepted: 12/03/2021] [Indexed: 01/26/2023]
Abstract
The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration, and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival, and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA. We found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis upon YAP1 suppression in YAP1-dependent cells, xenografts, and colon cancer organoids. YAP1 and PRDM14 individually activated the transcription of calmodulin 2 (CALM2) and a glucose transporter SLC2A1 upon YAP1 suppression, and CALM2 or SLC2A1 expression was required for the rescue of YAP1 suppression. Together, these findings implicate PRDM14-mediated transcriptional upregulation of CALM2 and SLC2A1 as key components of oncogenic YAP1 signaling and dependency.
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Affiliation(s)
- Miju Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Seav Huong Ly
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Yingtian Xie
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Gina N Duronio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Dane Ford-Roshon
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Justin H Hwang
- Masonic Cancer Center and Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA
| | - Rita Sulahian
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jonathan P Rennhack
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jonathan So
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Ole Gjoerup
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Jessica A Talamas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | | | - Henry W Long
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - John G Doench
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Nilay S Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - William C Hahn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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26
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Feng M, Dong N, Zhou X, Ma L, Xiang R. Myosin light chain 9 promotes the proliferation, invasion, migration and angiogenesis of colorectal cancer cells by binding to Yes-associated protein 1 and regulating Hippo signaling. Bioengineered 2022; 13:96-106. [PMID: 34974798 PMCID: PMC8805887 DOI: 10.1080/21655979.2021.2008641] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Colorectal cancer is a common type of cancer with high incidence and poor prognosis. Increased expression of myosin light chain 9 (MYL9) has been reported in early-stage and recurrent colorectal cancer tissues. This study aimed to investigate the precise role of MYL9 on the progression of colorectal cancer. MYL9 expression in several colorectal cancer cell lines was detected by Western blotting and RT-qPCR. Following MYL9 overexpression or knockdown, MYL9 expression was determined via RT-qPCR. Cell proliferation was detected with Cell Counting Kit-8 assay. Cell invasion, migration and angiogenesis were, respectively, examined with transwell, wound healing and tube formation assays. The binding between MYL9 and Yes-associated protein 1 (YAP1) was verified by a co-immunoprecipitation assay. The expression of YAP1, connective tissue growth factor and cysteine-rich angiogenic inducer 61 was examined by Western blotting. Subsequently, YAP1 silencing or Hippo antagonist was performed to clarify the regulatory mechanisms of MYL9 in colorectal cancer progression. Experimental results showed that MYL9 expression was elevated in colorectal cancer cell lines. MYL9 overexpression promoted cell proliferation, invasion, migration and angiogenesis, while silencing of MYL9 exerted the opposite effects. Results of co-immunoprecipitation assay indicated that MYL9 could bind to YAP1. Further experiments revealed that MYL9 affected the expression of YAP1 and its downstream signaling proteins. Afterward, YAP1 knockdown or the addition of Hippo antagonist inhibited the proliferation, invasion, migration and angiogenesis of colorectal cancer cells. Overall, MYL9 promotes the proliferation, invasion, migration and angiogenesis of colorectal cancer cells by binding to YAP1 and thereby activating Hippo signaling.
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Affiliation(s)
- Min Feng
- Department of Gastroenterology, East Hospital of Zibo Central Hospital, Shandong Province, Zibo City, China
| | - Ningfei Dong
- Department of Gastroenterology, East Hospital of Zibo Central Hospital, Shandong Province, Zibo City, China
| | - Xin Zhou
- Department of Gastroenterology, East Hospital of Zibo Central Hospital, Shandong Province, Zibo City, China
| | - Lihong Ma
- Department of Gastroenterology, West Hospital of Zibo Central Hospital, Zibo, Shandong Province, China
| | - Rui Xiang
- Department of Gastroenterology, West Hospital of Zibo Central Hospital, Zibo, Shandong Province, China
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27
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Casati G, Giunti L, Iorio AL, Marturano A, Galli L, Sardi I. Hippo Pathway in Regulating Drug Resistance of Glioblastoma. Int J Mol Sci 2021; 22:ijms222413431. [PMID: 34948224 PMCID: PMC8705144 DOI: 10.3390/ijms222413431] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 11/30/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.
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Affiliation(s)
- Giacomo Casati
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
- Correspondence:
| | - Laura Giunti
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Anna Lisa Iorio
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Arianna Marturano
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
| | - Luisa Galli
- Infectious Disease Unit, Department of Health Sciences, University of Florence, 50139 Florence, Italy;
| | - Iacopo Sardi
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (L.G.); (A.L.I.); (A.M.); (I.S.)
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28
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Passi M, Zahler S. Mechano-Signaling Aspects of Hepatocellular Carcinoma. J Cancer 2021; 12:6411-6421. [PMID: 34659531 PMCID: PMC8489129 DOI: 10.7150/jca.60102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/11/2021] [Indexed: 12/13/2022] Open
Abstract
HCC is one of the leading causes of cancer related death worldwide and comprises about 90% of the cases of primary liver cancer. It is generally accompanied by chronic liver fibrosis characterised by deposition of collagen fibres, which, in turn, causes enhanced stiffness of the liver tissue. Changes of tissue stiffness give rise to alterations of signalling pathways that are associated to mechanical properties of the cells and the extracellular matrix, and that can be subsumed as "mechano-signaling pathways", like, e.g., the YAP/TAZ pathway, or the SRF pathway. Stiffness of the liver tissue modulates mechanical regulation of many genes involved in HCC progression. However, mechano-signaling is still rather underrepresented in our concepts of cancer in comparison to "classical" biochemical signalling pathways. This review aims to give an overview of various stiffness induced mechano-biological aspects of HCC.
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Affiliation(s)
- Mehak Passi
- Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr. 5-13, 81377 Munich, Germany
| | - Stefan Zahler
- Center for Drug Research, Ludwig-Maximilians-University, Butenandtstr. 5-13, 81377 Munich, Germany
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29
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Kim J, Jang J, Cho DW. Recapitulating the Cancer Microenvironment Using Bioprinting Technology for Precision Medicine. MICROMACHINES 2021; 12:1122. [PMID: 34577765 PMCID: PMC8472267 DOI: 10.3390/mi12091122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/09/2021] [Accepted: 09/15/2021] [Indexed: 12/20/2022]
Abstract
The complex and heterogenous nature of cancer contributes to the development of cancer cell drug resistance. The construction of the cancer microenvironment, including the cell-cell interactions and extracellular matrix (ECM), plays a significant role in the development of drug resistance. Traditional animal models used in drug discovery studies have been associated with feasibility issues that limit the recapitulation of human functions; thus, in vitro models have been developed to reconstruct the human cancer system. However, conventional two-dimensional and three-dimensional (3D) in vitro cancer models are limited in their ability to emulate complex cancer microenvironments. Advances in technologies, including bioprinting and cancer microenvironment reconstruction, have demonstrated the potential to overcome some of the limitations of conventional models. This study reviews some representative bioprinted in vitro models used in cancer research, particularly fabrication strategies for modeling and consideration of essential factors needed for the reconstruction of the cancer microenvironment. In addition, we highlight recent studies that applied such models, including application in precision medicine using advanced bioprinting technologies to fabricate biomimetic cancer models. Furthermore, we discuss current challenges in 3D bioprinting and suggest possible strategies to construct in vitro models that better mimic the pathophysiology of the cancer microenvironment for application in clinical settings.
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Affiliation(s)
- Jisoo Kim
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
| | - Jinah Jang
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Department of Creative IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, Korea
| | - Dong-Woo Cho
- School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, Korea
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30
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Zhou L, Wang J, Liu J, Liang J, Wang Y, Cai Q, Huang Y. YAP activation attenuates toxicarioside G‑induced lethal autophagy arrest in SW480 colorectal cancer cells. Oncol Rep 2021; 46:224. [PMID: 34458926 PMCID: PMC8424488 DOI: 10.3892/or.2021.8175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Toxicarioside G (TCG), a natural product isolated from Calotropis gigantea, has been found to exhibit potent anticancer effects. The present study aimed to investigate the effect of TCG on the SW480 colorectal cancer cell line and the role of autophagy and Yes1 associated transcriptional regulator (YAP) in the TCG-mediated inhibition of cell proliferation and viability. Cell proliferation was detected using MTT, BrdU, colony formation and LDH release assays, while apoptosis was analyzed using flow cytometry and western blot analyses. Immunofluorescence and western blot analysis was used to determine TCG-induced autophagy and YAP activation. Pharmacological inhibition and siRNA was used to investigate the role of autophagy and YAP in TCG-mediated cell growth inhibition. The results revealed that TCG inhibited SW480 cell proliferation and viability, independent of apoptosis, and also induced autophagy. It was further demonstrated that TCG blocks autophagic flux, resulting in autophagy arrest in the SW480 cell line. The inhibition of autophagy restored the TCG-mediated inhibition of cell proliferation and viability, suggesting that TCG may induce lethal autophagy arrest in the SW480 cell line. Furthermore, TCG induced YAP activation in the SW480 cell line. Inhibition of YAP activity enhanced the TCG-mediated inhibition of cell proliferation and viability, suggesting that YAP may play a protective role in the TCG-induced effects. In conclusion, the findings of the present study indicated that TCG may induce lethal autophagy arrest and activate YAP, which serves a protective role in the SW480 cell line. These results suggested that the combined targeting of TCG and YAP may represent a promising strategy for TCG-mediated anticancer therapy.
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Affiliation(s)
- Limin Zhou
- Key Laboratory of Tropical Translational Medicine of The Ministry of Education and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Jinyan Wang
- Key Laboratory of Tropical Translational Medicine of The Ministry of Education and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Jiaqi Liu
- Key Laboratory of Tropical Translational Medicine of The Ministry of Education and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Jiantang Liang
- Key Laboratory of Tropical Translational Medicine of The Ministry of Education and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Yansong Wang
- Hainan Haitai Biomedical Technology Co., Ltd., Haikou, Hainan 571199, P.R. China
| | - Qunfang Cai
- School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Yonghao Huang
- Key Laboratory of Tropical Translational Medicine of The Ministry of Education and Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
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31
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Jiang L, Zhang J, Xu Q, Wang B, Yao Y, Sun L, Wang X, Zhou D, Gao L, Song S, Zhu X. YAP promotes the proliferation and migration of colorectal cancer cells through the Glut3/AMPK signaling pathway. Oncol Lett 2021; 21:312. [PMID: 33692844 PMCID: PMC7933749 DOI: 10.3892/ol.2021.12573] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/02/2021] [Indexed: 12/16/2022] Open
Abstract
Yes-associated protein (YAP), as a major downstream effector in the Hippo signaling pathway, is considered as an oncogene in cancer. The present study aimed to investigate the potential role of YAP in the development and progression of colorectal cancer (CRC). The mRNA and protein expression levels of YAP in human CRC tissue samples and adjacent normal tissue were analyzed using public databases, as well as clinical samples. The potential roles of YAP and the underlying mechanism regulating the proliferation and migration of CRC cells were examined using genetic manipulation in vitro. The correlation between the expression of the YAP gene and epithelial-to-mesenchymal transition (EMT) markers was investigated in order to determine the mechanism underlying the observed effects of YAP. YAP mRNA expression levels were significantly upregulated in CRC tissue compared with in normal tissue, as determined using datasets obtained from Oncomine. Similarly, in clinical samples, the protein expression levels of YAP were significantly upregulated in CRC tissue samples compared with in normal tissue samples. YAP knockdown inhibited the proliferation and migration of CRC cells in vitro, whereas its overexpression resulted in the opposite effect. The expression levels of the YAP gene were positively correlated with those of EMT markers (such as vimentin and N-cadherin) and EMT-inducing transcription factors (such as Snail1, Slug and zinc finger E-box binding homeobox 1 and 2) in CRC samples from Gene Expression Profiling Interactive Analysis. Furthermore, YAP silencing increased the protein expression of E-cadherin and decreased that of vimentin in CRC cells. By contrast, the overexpression of YAP had the opposite effect. YAP promoted the glucose transporter 3 (Glut3)/AMP-activated protein kinase (AMPK) signaling pathway in CRC cells. In conclusion, YAP promoted the proliferation and migration of CRC cells, as well as the expression of EMT markers, possibly by regulating the Glut3/AMPK signaling pathway.
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Affiliation(s)
- Linhua Jiang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jiawen Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Qixuan Xu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Bin Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yizhou Yao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Liang Sun
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xuchao Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Diyuan Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Ling Gao
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Shiduo Song
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xinguo Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Li Y, Sun C, Tan Y, Zhang H, Li Y, Zou H. ITGB1 enhances the Radioresistance of human Non-small Cell Lung Cancer Cells by modulating the DNA damage response and YAP1-induced Epithelial-mesenchymal Transition. Int J Biol Sci 2021; 17:635-650. [PMID: 33613118 PMCID: PMC7893583 DOI: 10.7150/ijbs.52319] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/27/2020] [Indexed: 12/13/2022] Open
Abstract
Objectives: Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. Materials and Methods: The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. Results: ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. Conclusions: ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.
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Affiliation(s)
- Yuexian Li
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Cheng Sun
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Yonggang Tan
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Heying Zhang
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
| | - Yuchao Li
- School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases
| | - Huawei Zou
- Department of Oncology, Shengjing Hospital affiliated with China Medical University, Shenyang 110004, China
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Eshghifar N, Badrlou E, Pouresmaeili F. The roles of miRNAs' clinical efficiencies in the colorectal cancer pathobiology: A review article. Hum Antibodies 2020; 28:273-285. [PMID: 32623393 DOI: 10.3233/hab-200417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
MiRNAs (microRNAs) are defined as micro directors and regulators of gene expression. Since altered miRNA expression is signified in the pathobiology of diverse cancers such as colorectal cancers (CRCs), these molecules are described as therapeutic targets, either. Manipulation of miRNAs could lead to further therapy for chemo and radio-resistant CRCs. The usage of microRNAs has indicated prominent promise in the prognosis and diagnosis of CRC, because of their unique expression pattern associated with cancer types and malignancies. Nowadays, many researchers are analyzing the correlation between miRNA polymorphisms and cancer risk. With continuous incompatibility in colorectal cancer (CRC) miRNAs expression data, it is critical to move toward the content of a "pre-laboratory" analysis to speed up efficient accuracy medicine and translational study. Pathway study for the highest expressed miRNAs- regulated target genes resulted in the identification of a considerable number of genes associated with CRC pathway including PI3K, TGFβ, and APC. In this review, we aimed to collect fruitful information about miRNAs and their potential roles in CRC, and provide a meta-analysis of the most frequently studied miRNAs in association with the disease.
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Affiliation(s)
- Nahal Eshghifar
- Department of Molecular and Cellular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Badrlou
- Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farkhondeh Pouresmaeili
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Moon S, Lee S, Caesar JA, Pruchenko S, Leask A, Knowles JA, Sinon J, Chaqour B. A CTGF-YAP Regulatory Pathway Is Essential for Angiogenesis and Barriergenesis in the Retina. iScience 2020; 23:101184. [PMID: 32502964 PMCID: PMC7270711 DOI: 10.1016/j.isci.2020.101184] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/18/2020] [Accepted: 05/18/2020] [Indexed: 12/24/2022] Open
Abstract
Connective tissue growth factor (CTGF) or cellular communication network 2 (CCN2) is a matricellular protein essential for normal embryonic development and tissue repair. CTGF exhibits cell- and context-dependent activities, but CTGF function in vascular development and barrier function is unknown. We show that endothelial cells (ECs) are one of the major cellular sources of CTGF in the developing and adult retinal vasculature. Mice lacking CTGF expression either globally or specifically in ECs exhibit impaired vascular cell growth and morphogenesis and blood barrier breakdown. The global molecular signature of CTGF includes cytoskeletal and extracellular matrix protein, growth factor, and transcriptional co-regulator genes such as yes-associated protein (YAP). YAP, itself a transcriptional activator of CTGF, mediates several CTGF-controlled angiogenic and barriergenic transcriptional programs. Re-expression of YAP rescues, at least partially, angiogenesis and barriergenesis in CTGF mutant mouse retinas. Thus, the CTGF-YAP regulatory loop is integral to retinal vascular development and barrier function.
CTGF has a strong and persistent expression in the retinal vasculature Mice lacking CTGF exhibit defects in angiogenesis and blood barrier integrity CTGF-targeted genes include matrix, growth, and transcription co-factors like YAP YAP re-expression partly rescues angiogenic and barriergenic defects of CTGF loss
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Affiliation(s)
- Sohyun Moon
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Sangmi Lee
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Joy Ann Caesar
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Sarah Pruchenko
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Andrew Leask
- University of Saskatchewan, College of Dentistry, E3338 HS - 105 Wiggins Road, Saskatoon, SK S7N 5E4, Canada
| | - James A Knowles
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Jose Sinon
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA
| | - Brahim Chaqour
- State University of New York, Downstate Health Science University, Department of Cell Biology, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA; State University of New York, Downstate Health Science University, Department of Ophthalmology, 450 Clarkson Avenue, Brooklyn, NY 11203, USA; SUNY Eye Institute, SUNY Downstate Health Science University, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
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35
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Chen X, Kiss A, Schaff Z, Evert K, Zhang Y, Zhong S, Wang J, Evert M, Calvisi DF, Chen X. CDK9 is dispensable for YAP-driven hepatoblastoma development. Pediatr Blood Cancer 2020; 67:e28221. [PMID: 32124532 DOI: 10.1002/pbc.28221] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/29/2020] [Accepted: 01/30/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Hepatoblastoma (HB) is the most common pediatric liver malignancy, occurring mainly during the first 4 years of life. Recent studies unraveled the frequent, coordinated activation of Wnt/β-catenin and YAP/Hippo (where YAP is yes-associated protein) pathways in human HB samples. Furthermore, it was found that concomitant overexpression of activated forms of β-catenin and YAP in the mouse liver triggers HB formation in YAP/β-catenin mice. Cyclin-dependent kinases 9 (CDK9) is an elongating kinase, which has been shown to mediate YAP-driven tumorigenesis. The role of CDK9 in HB molecular pathogenesis has not been investigated to date. METHODS CDK9 expression was determined in human HB lesions, HB cell lines, and YAP/β-catenin mouse livers. CDK9 was silenced in human HB cell lines and the effects on growth rate and YAP targets were analyzed. Hydrodynamic transfection of YAPS127A and ∆N90-β-catenin together with either shCdk9 or control shLuc (where Luc is luciferase) plasmids was employed to assess the requirement of Cdk9 for HB development in vivo. RESULTS Nuclear immunoreactivity for CDK9 protein was more pronounced in human HB samples and YAP/β-catenin mouse HB tumor tissues than in corresponding surrounding nontumorous liver tissues. CDK9 protein was also expressed in human HB cell lines. Silencing of CDK9 in human HB cell lines did not lead to consistent effects on HB cell growth or YAP target gene expression. Surprisingly, silencing of Cdk9 led to accelerated liver tumorigenesis in YAP/β-catenin mice. CONCLUSION CDK9 is not a major downstream mediator of YAP oncogenic function in HB development and progression.
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Affiliation(s)
- Xinyan Chen
- Department of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Andras Kiss
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Schaff
- Second Department of Pathology, Semmelweis University, Budapest, Hungary
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Yi Zhang
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.,Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Ministry of Education, Chongqing University, Chongqing, China
| | - Sheng Zhong
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Jingxiao Wang
- School of Life Science, Beijing University of Chinese Medicine, Beijing, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
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Xu W, Zhou G, Wang H, Liu Y, Chen B, Chen W, Lin C, Wu S, Gong A, Xu M. Circulating lncRNA SNHG11 as a novel biomarker for early diagnosis and prognosis of colorectal cancer. Int J Cancer 2019; 146:2901-2912. [PMID: 31633800 DOI: 10.1002/ijc.32747] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 10/04/2019] [Accepted: 10/08/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality worldwide. Emerging evidence indicates that tumour cells release substantial amounts of RNA into the bloodstream, in which RNA strongly resists RNases and is present at sufficient levels for quantitative analyses. Our study aimed to discover blood-based markers for the early detection of CRC and to ascertain their efficiency in discriminating healthy controls, patients with polyps and adenomas and cancer patients. We first analysed and screened ZFAS1, SNHG11, LINC00909 and LINC00654 in a bioinformatics database and then collected clinical plasma samples for preliminary small-scale analysis and further large-scale verification. We then explored the mechanism of dominant lncRNA SNHG11 expression in CRC by in vitro and in vivo assays. The combination of ZFAS1, SNHG11, LINC00909 and LINC00654 showed high diagnostic performance for CRC (AUC: 0.937), especially early-stage disease (AUC: 0.935). Plasma levels of the four candidate lncRNAs were significantly reduced in postoperative samples compared to preoperative samples. A panel including these four lncRNAs performed well in distinguishing patient groups with different stages of colon disease, and SNHG11 exhibited the greatest diagnostic ability to identify precancerous lesions and early-stage tumour formation. Mechanistically, high SNHG11 expression promotes proliferation and metastasis by targeting the Hippo pathway. Taken together, the data indicate that SNHG11 may be a novel therapeutic target for the treatment of CRC and a potential biomarker for the early detection of CRC.
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Affiliation(s)
- Wei Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China.,Department of Clinical Psychology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Gai Zhou
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China.,Department of Gastroenterology, Nanjing Jiangbei People's Hospital, Nanjing, China
| | - Huizhi Wang
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Yawen Liu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Baoding Chen
- Department of Ultrasound, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Wei Chen
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Chen Lin
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Shuhui Wu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Aihua Gong
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Min Xu
- Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
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Human Colorectal Cancer from the Perspective of Mouse Models. Genes (Basel) 2019; 10:genes10100788. [PMID: 31614493 PMCID: PMC6826908 DOI: 10.3390/genes10100788] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/25/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.
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Two Opposing Faces of Retinoic Acid: Induction of Stemness or Induction of Differentiation Depending on Cell-Type. Biomolecules 2019; 9:biom9100567. [PMID: 31590252 PMCID: PMC6843238 DOI: 10.3390/biom9100567] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/01/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022] Open
Abstract
Stem cells have the capacity of self-renewal and, through proliferation and differentiation, are responsible for the embryonic development, postnatal development, and the regeneration of tissues in the adult organism. Cancer stem cells, analogous to the physiological stem cells, have the capacity of self-renewal and may account for growth and recurrence of tumors. Development and regeneration of healthy tissues and tumors depend on the balance of different genomic and nongenomic signaling pathways that regulate stem cell quiescence, proliferation, and differentiation. During evolution, this balance became dependent on all-trans retinoic acid (RA), a molecule derived from the environmental factor vitamin A. Here we summarize some recent findings on the prominent role of RA on the proliferation of stem and progenitor cells, in addition to its well-known function as an inductor of cell differentiation. A better understanding of the regulatory mechanisms of stemness and cell differentiation by RA may improve the therapeutic options of this molecule in regenerative medicine and cancer.
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39
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Tang D, Dai Y, Lin L, Xu Y, Liu D, Hong X, Jiang H, Xu S. STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling. Cancer Sci 2019; 110:3145-3156. [PMID: 31393050 PMCID: PMC6778644 DOI: 10.1111/cas.14166] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/29/2019] [Accepted: 08/05/2019] [Indexed: 12/11/2022] Open
Abstract
Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
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Affiliation(s)
- Dong‐E Tang
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Yong Dai
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Lie‐Wen Lin
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Yong Xu
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Dong‐Zhou Liu
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Xiao‐Ping Hong
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
| | - Hao‐Wu Jiang
- Department of Anesthesiology and Center for the Study of ItchWashington University School of MedicineSt. LouisMOUSA
| | - Song‐Hui Xu
- Department of Clinical Medical Research CenterThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital Southern, University of Science and Technology, Shenzhen People's HospitalShenzhenChina
- Department of Biochemistry, Marlene and Stewart Greenebaum Cancer CenterUniversity of Maryland School of MedicineBaltimoreMDUSA
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40
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Zhou W, Li Y, Song J, Li C. Fluorescence polarization assay for the identification and evaluation of inhibitors at YAP-TEAD protein-protein interface 3. Anal Biochem 2019; 586:113413. [PMID: 31479631 DOI: 10.1016/j.ab.2019.113413] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 07/31/2019] [Accepted: 08/29/2019] [Indexed: 01/06/2023]
Abstract
The Hippo signaling pathway controls cell-cell contact, cell proliferation, as well as organ size by integrating changes in the cellular microenvironment. In recent years, the pivotal role of Hippo signaling in cancers has been well recognized. Inhibition of the pathway promotes the translocation of the major Hippo pathway effectors, the yes-associated protein (YAP) and its paralog TAZ, to the nucleus, where they interact with the transcription factor family transcriptional enhancer associate domain (TEAD), thus coactivating the expression of downstream genes, leading to cell transformation, tissue overgrowth, and tumor development. Therefore, the interruption of the YAP-TEAD transcriptional complex represents a novel opportunity for the treatment of cancer. Here, we established a fluorescence polarization (FP)-based assay for the identification and evaluation of YAP-TEAD protein-protein interface (PPI) inhibitors at the YAP Ω-loop binding region of TEAD, which is also called interface 3 at the YAP-TEAD binding surface. Furthermore, a patented small molecule (Patent-22) was evaluated by the FP assay, which confirmed that it was a YAP-TEAD PPI inhibitor at interface 3. Possessing great application value, this FP method is reliable, robust, and economical for inhibitor assessment and drug discovery.
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Affiliation(s)
- Wei Zhou
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, 32610, United States
| | - Yiping Li
- Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, China
| | - Jinhua Song
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, United States
| | - Chenglong Li
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, 32610, United States; Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, United States; Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, United States.
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Chung SY, Huang WC, Chen ZS, Chao TC, Su Y. Elucidation of the mechanism underlying CD44v6-induced transformation of IEC-6 normal intestinal epithelial cells. J Cell Physiol 2019; 235:194-209. [PMID: 31219187 DOI: 10.1002/jcp.28959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 05/24/2019] [Indexed: 02/06/2023]
Abstract
The transformation abilities of CD44s and CD44v6 in normal intestinal epithelial cells have not yet been reported. Herein, we established both CD44s and CD44v6 overexpressing stable clones from rat IEC-6 cells and demonstrated that the CD44v6 clones had higher saturation density and anchorage independence. Additionally, CD44v6 clones were more resistant to oxaliplatin and irinotecan which might be attributed to a significantly increased B-cell lymphoma 2 level and a reduced DNA damage response in these cells. Moreover, c-Met and vascular endothelial growth factor receptor 2 signalings were involved in modulating the saturation density in CD44v6 clones. Interestingly, higher activation of both AKT and extracellular-signal-regulated kinase (ERK) were detected in CD44v6 clones which might account in part for the cell density-independent nuclear localization of Yes-associated protein (YAP). To no surprise, increases of both saturation density and anchorage independence in CD44v6 clones were markedly diminished by PI3K, AKT, MEK, and ERK inhibitors as well as YAP knockdown. By contrast, overexpression of a constitutively active YAP robustly increased the aforementioned phenotypes in IEC-6 cells. Collectively, our results suggest that upregulation of CD44v6, but not CD44s, induces the transformation of normal intestinal epithelial cells possibly via activating the c-Met/AKT/YAP pathway which might also explain the important role of CD44v6 in the initiation of various carcinomas.
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Affiliation(s)
- Shin-Yi Chung
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Wen-Chen Huang
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Zong-Siang Chen
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Ta-Chung Chao
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.,Faculty of Medicine, School of Medicine, National Yang-Min University, Taipei, Taiwan, ROC
| | - Yeu Su
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, ROC
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Zhou L, Cai L, Guo Y, Zhang H, Wang P, Yi G, Huang Y. Calotropin activates YAP through downregulation of LATS1 in colorectal cancer cells. Onco Targets Ther 2019; 12:4047-4054. [PMID: 31190898 PMCID: PMC6536122 DOI: 10.2147/ott.s200873] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/14/2019] [Indexed: 02/03/2023] Open
Abstract
Objectives: Calotropin (CTP), a natural product isolated from Calotropis gigantea, has been identified as a potential anticancer agent. In this study, we aimed to investigate the effect CTP on colorectal cancer and the role of Yes-associated protein (YAP) in CTP-inhibited cell proliferation. Methods: Cell viability and cell proliferation were detected by MTT and BrdU assay. Western blotting and immunofluorescence were performed to determine CTP-induced YAP dephosphorylation and nuclear localization. Western blotting, siRNA transfection and RT-PCR analysis were carried out to investigate the mechanisms of CTP-mediated YAP activation. The anti-tumor activities of CTP were observed in mice tumor models. Results: We demonstrated that CTP inhibits the proliferation of colorectal cancer cells both in vitro and in vivo. Moreover, we showed that CTP activates YAP in colorectal cancer cells. Mechanistically, CTP promotes LATS1 degradation via the ubiquitination/proteasome pathway, resulting in YAP dephosphorylation and nuclear localization, leading to induce YAP target genes expression in colorectal cancer cells. Inhibition of YAP activity enhances CTP-mediated inhibition of cell proliferation, suggesting that YAP plays a protective role in CTP-induced antiproliferative effect. Conclusion: Our results demonstrate that CTP markedly inhibits tumor growth and activates a protective role of YAP in colorectal cancer cells, indicating that combination of CTP and YAP targeting drugs may be a promising strategy for colorectal cancer treatment.
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Affiliation(s)
- Limin Zhou
- Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, People's Republic of China.,Public Research Laboratory, Hainan Medical College, Haikou 571199, People's Republic of China
| | - Luliang Cai
- Department of Pediatrics, Hainan Provincial People's Hospital, Haikou 570311, People's Republic of China
| | - Yanzi Guo
- Key Laboratory of Preclinical Pharmacology and Toxicology of Hainan Province, Hainan Medical College, Haikou 571199, People's Republic of China
| | - Huanyu Zhang
- Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, People's Republic of China
| | - Peng Wang
- Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, People's Republic of China
| | - Guohui Yi
- Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, People's Republic of China.,Public Research Laboratory, Hainan Medical College, Haikou 571199, People's Republic of China
| | - Yonghao Huang
- Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education & Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical College, Haikou 571199, People's Republic of China.,Department of Anesthesiology, Second Affiliated Hospital, Hainan Medical College, Haikou 571199, People's Republic of China
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43
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He C, Lv X, Huang C, Hua G, Ma B, Chen X, Angeletti PC, Dong J, Zhou J, Wang Z, Rueda BR, Davis JS, Wang C. YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis. EMBO Rep 2019; 20:e44948. [PMID: 30755404 PMCID: PMC6399607 DOI: 10.15252/embr.201744948] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 01/09/2019] [Accepted: 01/10/2019] [Indexed: 12/16/2022] Open
Abstract
Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 in hOSEs prevents these cells from natural replicative and YAP1-induced senescence. Most importantly, loss of LATS2 switches ovarian cells from YAP-induced senescence to malignant transformation. Our results demonstrate that LATS2 and YAP1, two major components of the Hippo/YAP signaling pathway, form a negative feedback loop to control YAP1 activity and prevent ovarian cells from malignant transformation. Human cancer genomic data extracted from TCGA datasets further confirm the clinical relevance of our finding.
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Affiliation(s)
- Chunbo He
- Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xiangmin Lv
- Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Cong Huang
- Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Guohua Hua
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Bowen Ma
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Xingcheng Chen
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Peter C Angeletti
- Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Jixin Dong
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jin Zhou
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- Department of Obstetrics and gynecology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Zhengfeng Wang
- College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bo R Rueda
- Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
| | - John S Davis
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- Omaha Veterans Affairs Medical Center, Omaha, NE, USA
| | - Cheng Wang
- Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA
- Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
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44
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Kaowinn S, Yawut N, Koh SS, Chung YH. Cancer upregulated gene (CUG)2 elevates YAP1 expression, leading to enhancement of epithelial-mesenchymal transition in human lung cancer cells. Biochem Biophys Res Commun 2019; 511:122-128. [PMID: 30771899 DOI: 10.1016/j.bbrc.2019.02.036] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/07/2019] [Indexed: 12/22/2022]
Abstract
Although our previous studies have showed that a novel oncogene, cancer upregulated gene (CUG)2 induced epithelial-mesenchymal transition (EMT), the detailed molecular mechanism remains unknown. Because several lines of evidence documented that Yes-Associated Protein (YAP)1 is closely associated with cancer stem cell (CSC)-like phenotypes including EMT, stemness, and drug resistance, we wondered if YAP1 is involved in CUG2-induced EMT. We herein found that the overexpression of CUG2 increased YAP1 expression at the transcriptional as well as protein levels. Chromatin immunoprecipitation assay revealed that the elevated YAP1 transcripts are attributed to c-Jun and AP2 bindings to the YAP1 promoter. Akt and MAPK kinases including ERK, JNK, and p38 MAPK enhanced the level of YAP1 protein. In spite of a close relationship between β-catenin and YAP1, not β-catenin but NEK2 played the role in increasing YAP1 expression. Silencing YAP1 inhibited CUG2-induced cell migration and invasion. N-cadherin and vimentin expressions were decreased during YAP1 knockdown. The suppression of YAP1 diminished TGF-β transcriptional activity and expression as well as phosphorylation level of Smad2 and Twist protein. Conversely, LY2109761 or Smad2 siRNA treatment reduced YAP1 protein levels, indicating a close interplay between YAP1 and TGF-β signaling. Taken together, we suggest that CUG2 induces up-regulation of YAP1 expression, leading to enhancing CUG2-induced EMT via a close crosstalk between YAP1 and TGF-β signaling.
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Affiliation(s)
- Sirichat Kaowinn
- BK21 Plus, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 46241, Republic of Korea
| | - Natpaphan Yawut
- BK21 Plus, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 46241, Republic of Korea
| | - Sang Seok Koh
- Department of Biosciences, Dong-A University, Busan, 49315, Republic of Korea
| | - Young-Hwa Chung
- BK21 Plus, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, 46241, Republic of Korea.
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45
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Guo L, Chen Y, Luo J, Zheng J, Shao G. YAP1 overexpression is associated with poor prognosis of breast cancer patients and induces breast cancer cell growth by inhibiting PTEN. FEBS Open Bio 2019; 9:437-445. [PMID: 30868052 PMCID: PMC6396162 DOI: 10.1002/2211-5463.12597] [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: 09/19/2018] [Revised: 11/11/2018] [Accepted: 12/10/2018] [Indexed: 01/09/2023] Open
Abstract
YES‐associated protein 1 (YAP1) plays a key role as a transcriptional coactivator in the Hippo tumor suppressor pathway. YAP1 is overexpressed in a variety of cancers and is considered to be encoded by a proto‐oncogene. However, the role of YAP1 remains debatable, because both gain and loss of YAP1 expression have both been reported in breast cancer (BC). Here, we found that elevated expression of YAP1 mRNA in BC was negatively correlated with relapse‐free, distant metastases‐free and overall survival rates. We then knocked down or overexpressed YAP1 in human BC cells, and examined cell proliferation, apoptosis, and tumorigenic ability in vivo. We identified that YAP1 promotes cell growth and inhibits cell apoptosis of BC through the phosphatase and tensin homolog deleted on chromosome 10–AKT signaling pathway, and thus suggest that YAP1 might serve as a new target for inhibiting BC progression.
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Affiliation(s)
- Liwen Guo
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Yutang Chen
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Jun Luo
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Jiaping Zheng
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
| | - Guoliang Shao
- Department of Interventional Radiology Zhejiang Cancer Hospital Hangzhou China
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46
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Li Y, Wang S, Wei X, Zhang S, Song Z, Chen X, Zhang J. Role of inhibitor of yes-associated protein 1 in triple-negative breast cancer with taxol-based chemoresistance. Cancer Sci 2019; 110:561-567. [PMID: 30467925 PMCID: PMC6361558 DOI: 10.1111/cas.13888] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 11/17/2018] [Accepted: 11/20/2018] [Indexed: 12/11/2022] Open
Abstract
Triple‐negative breast cancer (TNBC) is highly clinically aggressive and taxol‐based chemoresistance remains a big TNBC therapeutic problem to be solved. Verteporfin, a small molecular yes‐associated protein 1 (YAP1) inhibitor, is little known as an antitumor drug for TNBC. Our data showed that YAP1 expression was associated with early relapse in tissue samples of patients with TNBC taxol chemoresistance (P < .001). Verteporfin reduced migration and enhanced apoptosis or autophagy of a taxol‐resistant MDA‐MB‐231 cell line in vitro. Knockdown of YAP1 increased epithelial‐mesenchymal transition response in a taxol‐resistant TNBC cell line. In an in vivo experiment, we found that verteporfin was able to shrink tumor weight and volume and decreased Ki67 expression in a taxol‐resistant mouse model. Our results provide evidence that verteporfin could be a chemosensitizer for TNBC patients with taxol‐based treatment.
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Affiliation(s)
- Ying Li
- The Third Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Shunan Wang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, China
| | - Xi Wei
- Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Sheng Zhang
- The Third Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Zian Song
- The Third Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Xiao Chen
- The Third Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
| | - Jin Zhang
- The Third Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China
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47
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Immunohistochemical Profile of Tumor Suppressor Proteins RASSF1A and LATS1/2 in Relation to p73 and YAP Expression, of Human Inflammatory Bowel Disease and Normal Intestine. Pathol Oncol Res 2019; 26:567-574. [DOI: 10.1007/s12253-018-00575-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 12/21/2018] [Indexed: 01/07/2023]
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48
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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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49
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Shao Q, Xu J, Deng R, Wei W, Zhou B, Yue C, Zhu M, Zhu H. The expressions of YAP1, β-catenin and survivin in colon cancer tissues and their clinical significance. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:6032-6038. [PMID: 31949692 PMCID: PMC6963090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 10/26/2018] [Indexed: 06/10/2023]
Abstract
We aimed to evaluate the effects of YAP1, β-catenin, and survivin on the onset and progression of colon cancer, and to explore their correlations. The expressions of YAP1, β-catenin, and survivin in 106 colon cancer tissues and 55 normal colon mucosa tissues were measured by immunohistochemical assay. The correlations between their expressions and clinical and pathological characteristics were analyzed. The expression rates of YAP1, β-catenin, and survivin in colon cancer tissues were significantly higher than those in normal colon mucosa tissues (P<0.001). The expressions of YAP1, β-catenin, and survivin in colon cancer were correlated with neither gender nor age (P>0.05), but with the degree of differentiation, depth of invasion, lymph node metastasis and Duke's stage (P<0.05). Pearson's correlation analysis showed that the expressions of YAP1, β-catenin, and survivin in colon cancer tissues were all positively correlated (P<0.05). The overexpression of YAP1, β-catenin, and survivin played an important role in the onset and progression of colon cancer, providing reference value for prognosis prediction.
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Affiliation(s)
- Qianwen Shao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province HospitalGuangzhou Road 300, Nanjing 210029, Jiangsu Province, China
| | - Jing Xu
- Genetic Testing Center, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province HospitalGuangzhou Road 300, Nanjing 210029, Jiangsu Province, China
| | - Rong Deng
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
| | - Wei Wei
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
| | - Bing Zhou
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
| | - Chao Yue
- Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
| | - Miaoling Zhu
- Department of Pathology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
| | - Haitao Zhu
- Colorectal Cancer Center, Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjing, Jiangsu Province, China
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50
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Gao J, Zhang Y, Chen H, Chen Q, Feng D, Zhang L, Li C. Computational insights into the interaction mechanism of transcription cofactor vestigial-like protein 4 binding to TEA domain transcription factor 4 by molecular dynamics simulation and molecular mechanics generalized Born/surface area) calculation. J Biomol Struct Dyn 2018; 37:2538-2545. [PMID: 30051771 DOI: 10.1080/07391102.2018.1491889] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Hippo pathway has been implicated in the suppression of tissue overgrowth and tumor formation by restricting the oncogenic activity of Yes-associated protein (YAP). Transcription cofactor vestigial-like protein 4 (VGLL4), a natural YAP antagonist that competes with YAP for TEA domain transcription factor 4 (TEAD4) binding is a potential tumor suppressor in human gastric cancer. Comparing with the full length of VGLL4, the Tondu 2 domain of VGLL4 alone is fully functional in inhibiting YAP-induced TEAD4 reporter activity. Revealing the details of binding interaction between VGLL4 and TEAD4 would accelerate the discovery of improved drugs against YAP-driven human cancers. We investigated systematically the interaction mechanisms between TEAD4 and VGLL4 by molecular dynamics (MD) simulation, free energy calculation, and free energy decomposition analysis. Our simulations show that two loops of VGLL4 (residues 218-222 and 251-252) have little binding contribution on VGLL4 binding to TEAD4. The β1 strand of VGLL4 plays important role in the contribution to the binding, whereas the α3 helix gives small contribution. More interestingly, the mutation of several residues of α2 helix to alanine results in the contribution of α2 helix decreasing, accompanied by the increased binding contribution of α3 helix. Deletion of the β1 or α3 segment of VGLL4 has slight effect on the remaining two segments. Our simulation is well consistent with the in vivo evaluation of the binding of biotinylated VGLL4 peptides to TEAD4 in HepG2 cells by immunological approaches. We expect this work can provide valuable information for design of improved VGLL4 derivative anticancer peptides. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Jian Gao
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Yiran Zhang
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Han Chen
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Qingqing Chen
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Dingding Feng
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Ling Zhang
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
| | - Chenglin Li
- a Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy , Xuzhou Medical University , Xuzhou , Jiangsu , P. R. China Communicated by Ramaswamy H. Sarma
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