|
1
|
Abidi SNF, Chan S, Seidel K, Lafkas D, Vermeulen L, Peale F, Siebel CW. The Jag2/Notch1 signaling axis promotes sebaceous gland differentiation and controls progenitor proliferation. eLife 2024; 13:RP98747. [PMID: 39585329 PMCID: PMC11588336 DOI: 10.7554/elife.98747] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024] Open
Abstract
The sebaceous gland (SG) is a vital appendage of the epidermis, and its normal homeostasis and function is crucial for effective maintenance of the skin barrier. Notch signaling is a well-known regulator of epidermal differentiation, and has also been shown to be involved in postnatal maintenance of SGs. However, the precise role of Notch signaling in regulating SG differentiation in the adult homeostatic skin remains unclear. While there is evidence to suggest that Notch1 is the primary Notch receptor involved in regulating the differentiation process, the ligand remains unknown. Using monoclonal therapeutic antibodies designed to specifically inhibit of each of the Notch ligands or receptors, we have identified the Jag2/Notch1 signaling axis as the primary regulator of sebocyte differentiation in mouse homeostatic skin. Mature sebocytes are lost upon specific inhibition of the Jag2 ligand or Notch1 receptor, resulting in the accumulation of proliferative stem/progenitor cells in the SG. Strikingly, this phenotype is reversible, as these stem/progenitor cells re-enter differentiation when the inhibition of Notch activity is lifted. Thus, Notch activity promotes correct sebocyte differentiation, and is required to restrict progenitor proliferation.
Collapse
Affiliation(s)
| | - Sara Chan
- Department of Research Pathology, GenentechSan FranciscoUnited States
| | - Kerstin Seidel
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Daniel Lafkas
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Louis Vermeulen
- Department of Discovery Oncology, GenentechSan FranciscoUnited States
| | - Frank Peale
- Department of Research Pathology, GenentechSan FranciscoUnited States
| | | |
Collapse
|
|
2
|
Chen Y, Zhang XF, Ou-Yang L. Inferring cancer common and specific gene networks via multi-layer joint graphical model. Comput Struct Biotechnol J 2023; 21:974-990. [PMID: 36733706 PMCID: PMC9873583 DOI: 10.1016/j.csbj.2023.01.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 01/08/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Cancer is a complex disease caused primarily by genetic variants. Reconstructing gene networks within tumors is essential for understanding the functional regulatory mechanisms of carcinogenesis. Advances in high-throughput sequencing technologies have provided tremendous opportunities for inferring gene networks via computational approaches. However, due to the heterogeneity of the same cancer type and the similarities between different cancer types, it remains a challenge to systematically investigate the commonalities and specificities between gene networks of different cancer types, which is a crucial step towards precision cancer diagnosis and treatment. In this study, we propose a new sparse regularized multi-layer decomposition graphical model to jointly estimate the gene networks of multiple cancer types. Our model can handle various types of gene expression data and decomposes each cancer-type-specific network into three components, i.e., globally shared, partially shared and cancer-type-unique components. By identifying the globally and partially shared gene network components, our model can explore the heterogeneous similarities between different cancer types, and our identified cancer-type-unique components can help to reveal the regulatory mechanisms unique to each cancer type. Extensive experiments on synthetic data illustrate the effectiveness of our model in joint estimation of multiple gene networks. We also apply our model to two real data sets to infer the gene networks of multiple cancer subtypes or cell lines. By analyzing our estimated globally shared, partially shared, and cancer-type-unique components, we identified a number of important genes associated with common and specific regulatory mechanisms across different cancer types.
Collapse
Affiliation(s)
- Yuanxiao Chen
- Guangdong Key Laboratory of Intelligent Information Processing, Shenzhen Key Laboratory of Media Security, and Guangdong Laboratory of Artificial Intelligence and Digital Economy(SZ), Shenzhen University, Shenzhen, China
| | - Xiao-Fei Zhang
- School of Mathematics and Statistics & Hubei Key Laboratory of Mathematical Sciences, Central China Normal University, Wuhan, China
| | - Le Ou-Yang
- Guangdong Key Laboratory of Intelligent Information Processing, Shenzhen Key Laboratory of Media Security, and Guangdong Laboratory of Artificial Intelligence and Digital Economy(SZ), Shenzhen University, Shenzhen, China,Corresponding author.
| |
Collapse
|
|
3
|
Lin Q, Cao J, Du X, Yang K, Shen Y, Wang W, Klocker H, Shi J, Zhang J. The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer. Front Oncol 2022; 11:787953. [PMID: 35096586 PMCID: PMC8789881 DOI: 10.3389/fonc.2021.787953] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/13/2021] [Indexed: 01/14/2023] Open
Abstract
Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.
Collapse
Affiliation(s)
- Qimei Lin
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
| | - Jiasong Cao
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Nankai University, Tianjin, China
| | - Xiaoling Du
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
| | - Kuo Yang
- Department of Urology of the Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yongmei Shen
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Nankai University, Tianjin, China
| | - Weishu Wang
- State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Helmut Klocker
- Department of Urology, Division of Experimental Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Jiandang Shi
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Ju Zhang
- Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Laboratory of the Ministry of Education, Nankai University, Tianjin, China
| |
Collapse
|
|
4
|
Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix-Loop-Helix Transcription Factors. Int J Mol Sci 2021; 22:ijms222312855. [PMID: 34884664 PMCID: PMC8657788 DOI: 10.3390/ijms222312855] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 01/01/2023] Open
Abstract
The basic helix–loop–helix transcription factor (bHLH TF) family is involved in tissue development, cell differentiation, and disease. These factors have transcriptionally positive, negative, and inactive functions by combining dimeric interactions among family members. The best known bHLH TFs are the E-protein homodimers and heterodimers with the tissue-specific TFs or ID proteins. These cooperative and dynamic interactions result in a complex transcriptional network that helps define the cell’s fate. Here, the reported dimeric interactions of 67 vertebrate bHLH TFs with other family members are summarized in tables, including specifications of the experimental techniques that defined the dimers. The compilation of these extensive data underscores homodimers of tissue-specific bHLH TFs as a central part of the bHLH regulatory network, with relevant positive and negative transcriptional regulatory roles. Furthermore, some sequence-specific TFs can also form transcriptionally inactive heterodimers with each other. The function, classification, and developmental role for all vertebrate bHLH TFs in four major classes are detailed.
Collapse
|
|
5
|
The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation. Cells 2021; 10:cells10113215. [PMID: 34831437 PMCID: PMC8620267 DOI: 10.3390/cells10113215] [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: 08/20/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Basal cells (BCs) are stem/progenitor cells of the mucociliary airway epithelium, and their differentiation is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are unknown. Overexpression of the active NOTCH3 intracellular domain (NICD3) in primary human bronchial epithelial cells (HBECs) on in vitro air–liquid interface culture promoted club cell differentiation. Bulk RNA-seq analysis identified 692 NICD3-responsive genes, including the classical NOTCH target HEYL, which increased in response to NICD3 and positively correlated with SCGB1A1 (club cell marker) expression. siRNA knockdown of HEYL decreased tight junction formation and cell proliferation. Further, HEYL knockdown reduced club, goblet and ciliated cell differentiation. In addition, we observed decreased expression of HEYL in HBECs from donors with chronic obstructive pulmonary disease (COPD) vs. normal donors which correlates with the impaired differentiation capacity of COPD cells. Finally, overexpression of HEYL in COPD HBECs promoted differentiation into club, goblet and ciliated cells, suggesting the impaired capacity of COPD cells to generate a normal airway epithelium is a reversible phenotype that can be regulated by HEYL. Overall, our data identify the NOTCH3 downstream target HEYL as a key regulator of airway epithelial differentiation.
Collapse
|
|
6
|
Li C, Hou X, Yuan S, Zhang Y, Yuan W, Liu X, Li J, Wang Y, Guan Q, Zhou Y. High expression of TREM2 promotes EMT via the PI3K/AKT pathway in gastric cancer: bioinformatics analysis and experimental verification. J Cancer 2021; 12:3277-3290. [PMID: 33976737 PMCID: PMC8100818 DOI: 10.7150/jca.55077] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 03/15/2021] [Indexed: 01/17/2023] Open
Abstract
Background: To date, the pathogenesis of gastric cancer (GC) remains unclear. We combined public database resources and bioinformatics analysis methods, explored some novel genes and verified the experiments to further understand the pathogenesis of GC and to provide a promising target for anti-tumor therapy. Methods: We downloaded the chip data related to GC from the Gene Expression Omnibus (GEO) database, extracted differentially expressed genes (DEGs), and then determined the key genes in the development of GC via PPI networks and model analysis. Functional annotation via GO and KEGG enrichment of DEGs was used to understand the latent roles of DEGs. The expression of the triggering receptor expressed on myeloid cells 2 (TREM2) gene in GC cell lines was verified via RT-PCR and western blotting. Moreover, the CCK-8, wound healing assay, and transwell migration and invasion assays were used to understand the changes in the proliferation, migration, and invasion abilities of GC cells after silencing TREM2. Western blotting verified the interaction between TREM2 and PI3K predict of the string website, as well as the effect of TREM2 on EMT. Finally, a lung metastasis model was used to explore the relationship between TREM2 and metastasis. Results: Our study identified 16 key genes, namely BGN, COL1A1, COL4A1, COL5A2, NOX4, SPARC, HEYL, SPP1, TIMP1, CTHRC1, TREM2, SFRP4, FBXO32, GPX3, KIF4A, and MMP9 genes associated with GC. The EMT-related pathway was the most significantly altered pathway. TREM2 expression was higher in GC cell lines and was remarkably associated with tumor invasion depth, TNM stage, histological grade, histological type, anatomic subdivision, and Helicobacter pylori state. Knockdown of TREM2 expression inhibited the proliferation, migration, and invasion of GC cells as well as the progression of EMT by PI3K/AKT signaling in vitro. In addition, lung metastasis were decreased in vivo. Conclusions: We identified some important genes associated with the progression of GC via public database analysis, explored and verified the effects of proto-oncogene TREM2 on EMT via the PI3K/AKT pathway. TREM2 may be a novel target in the GC therapy.
Collapse
Affiliation(s)
- Chunmei Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoming Hou
- Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Shuqiao Yuan
- Department of medical laboratory, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yigan Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Wenzhen Yuan
- Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xiaoguang Liu
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Rheumatology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Juan Li
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, China
| | - Yuping Wang
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| | - Quanlin Guan
- Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China.,Key Laboratory for Gastrointestinal Diseases of Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China
| |
Collapse
|
|
7
|
Weber S, Koschade SE, Hoffmann CM, Dubash TD, Giessler KM, Dieter SM, Herbst F, Glimm H, Ball CR. The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo. BMC Cancer 2019; 19:1181. [PMID: 31796022 PMCID: PMC6892194 DOI: 10.1186/s12885-019-6396-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 11/22/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND While colorectal cancer (CRC) patients with localized disease have a favorable prognosis, the five-year-survival rate in patients with distant spread is still below 15%. Hence, a detailed understanding of the mechanisms regulating metastasis formation is essential to develop therapeutic strategies targeting metastasized CRC. The notch pathway has been shown to be involved in the metastatic spread of various tumor entities; however, the impact of its target gene HEYL remains unclear so far. METHODS In this study, we functionally assessed the association between high HEYL expression and metastasis formation in human CRC. Therefore, we lentivirally overexpressed HEYL in two human patient-derived CRC cultures differing in their spontaneous metastasizing capacity and analyzed metastasis formation as well as tumor cell dissemination into the bone marrow after xenotransplantation into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. RESULTS HEYL overexpression decreased tumor cell dissemination and the absolute numbers of formed metastases in a sub-renal capsular spontaneous metastasis formation model, addressing all steps of the metastatic cascade. In contrast, metastatic capacity was not decreased following intrasplenic xenotransplantation where the cells are placed directly into the blood circulation. CONCLUSION These results suggest that HEYL negatively regulates metastasis formation in vivo presumably by inhibiting intravasation of metastasis-initiating cells.
Collapse
Affiliation(s)
- Sarah Weber
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium (DKTK) Frankfurt am Main, Frankfurt am Main, Germany.,Department of Hematology and Oncology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Sebastian E Koschade
- German Cancer Consortium (DKTK) Frankfurt am Main, Frankfurt am Main, Germany.,Department of Hematology and Oncology, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christopher M Hoffmann
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Taronish D Dubash
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Klara M Giessler
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian M Dieter
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany
| | - Friederike Herbst
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany
| | - Hanno Glimm
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany.,Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany.,German Cancer Consortium (DKTK) Dresden, Dresden, Germany
| | - Claudia R Ball
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Dresden, Germany. .,Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany.
| |
Collapse
|
|
8
|
Hilliard AT, Xie D, Ma Z, Snyder MP, Fernald RD. Genome-wide effects of social status on DNA methylation in the brain of a cichlid fish, Astatotilapia burtoni. BMC Genomics 2019; 20:699. [PMID: 31506062 PMCID: PMC6737626 DOI: 10.1186/s12864-019-6047-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/19/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Successful social behavior requires real-time integration of information about the environment, internal physiology, and past experience. The molecular substrates of this integration are poorly understood, but likely modulate neural plasticity and gene regulation. In the cichlid fish species Astatotilapia burtoni, male social status can shift rapidly depending on the environment, causing fast behavioral modifications and a cascade of changes in gene transcription, the brain, and the reproductive system. These changes can be permanent but are also reversible, implying the involvement of a robust but flexible mechanism that regulates plasticity based on internal and external conditions. One candidate mechanism is DNA methylation, which has been linked to social behavior in many species, including A. burtoni. But, the extent of its effects after A. burtoni social change were previously unknown. RESULTS We performed the first genome-wide search for DNA methylation patterns associated with social status in the brains of male A. burtoni, identifying hundreds of Differentially Methylated genomic Regions (DMRs) in dominant versus non-dominant fish. Most DMRs were inside genes supporting neural development, synapse function, and other processes relevant to neural plasticity, and DMRs could affect gene expression in multiple ways. DMR genes were more likely to be transcription factors, have a duplicate elsewhere in the genome, have an anti-sense lncRNA, and have more splice variants than other genes. Dozens of genes had multiple DMRs that were often seemingly positioned to regulate specific splice variants. CONCLUSIONS Our results revealed genome-wide effects of A. burtoni social status on DNA methylation in the brain and strongly suggest a role for methylation in modulating plasticity across multiple biological levels. They also suggest many novel hypotheses to address in mechanistic follow-up studies, and will be a rich resource for identifying the relationships between behavioral, neural, and transcriptional plasticity in the context of social status.
Collapse
Affiliation(s)
| | - Dan Xie
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA
| | - Zhihai Ma
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA
| | - Michael P. Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA
| | | |
Collapse
|
|
9
|
Kamińska A, Pardyak L, Marek S, Wróbel K, Kotula-Balak M, Bilińska B, Hejmej A. Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells. Andrology 2019; 8:457-472. [PMID: 31468707 DOI: 10.1111/andr.12691] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/24/2019] [Accepted: 07/14/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Notch signaling pathway is involved in contact-dependent communication between the cells of seminiferous epithelium, and its proper activity is important for undisturbed spermatogenesis. OBJECTIVES The aim was to assess the effect of Notch pathway inhibition on the expression of nuclear (AR) and membrane (ZIP9) androgen receptors and androgen-regulated genes, claudin-5 and claudin-11, in TM4 mouse Sertoli cell line. MATERIALS AND METHODS DAPT (γ-secretase inhibitor) treatment and recombination signal binding protein silencing were employed to reduce Notch signaling, whereas immobilized ligands were used to activate Notch pathway in TM4 cells. To reveal specific effect of each androgen receptor, AR or ZIP9 silencing was performed. RESULTS Notch pathway inhibition increased the expression of AR and ZIP9 mRNA and proteins (p < 0.01; p < 0.05) in TM4 cells, whereas incubation with Notch ligands, rDLL1 or rJAG1, reduced AR (p < 0.01; p < 0.001) and ZIP9 (p < 0.05; p < 0.01) expressions, respectively. Testosterone enhanced the expression of both receptors (p < 0.05; p < 0.01). Androgen-regulated claudin-5 and claudin-11 (p < 0.01; p < 0.001) and cAMP (p < 0.001) were elevated in Notch-inhibited cells, while activation of Notch signaling by DLL1 or JAG1 reduced claudin-11 or claudin-5 level (p < 0.01; p < 0.001), respectively. DISCUSSION Our findings indicate opposite effect of Notch and androgen signaling on the expression of androgen receptors in TM4 cells. We demonstrated that AR expression is regulated by DLL1-mediated Notch signaling, whereas JAG1 is involved in the regulation of ZIP9. The expression of both claudins and cAMP production is under inhibitory influence of Notch pathway. The effects of Notch signaling on claudin-5 and claudin-11 expression are mediated by ZIP9 and AR, respectively. CONCLUSION Notch signaling may be considered as an important pathway controlling Sertoli cell physiology, and its alterations may contribute to disturbed response of Sertoli cells to androgens.
Collapse
Affiliation(s)
- A Kamińska
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| | - L Pardyak
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| | - S Marek
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| | - K Wróbel
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| | - M Kotula-Balak
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland.,University Centre of Veterinary Medicine, University of Agriculture in Krakow, Krakow, Poland
| | - B Bilińska
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| | - A Hejmej
- Department of Endocrinology, Faculty of Biology, Institute of Zoology & Biomedical Research, Jagiellonian University, Krakow, Poland
| |
Collapse
|
|
10
|
Ahmed AA, Robinson T, Palande M, Escara-Wilke J, Dai J, Keller ET. Targeted Notch1 inhibition with a Notch1 antibody, OMP-A2G1, decreases tumor growth in two murine models of prostate cancer in association with differing patterns of DNA damage response gene expression. J Cell Biochem 2019; 120:16946-16955. [PMID: 31099068 DOI: 10.1002/jcb.28954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 04/23/2019] [Accepted: 04/24/2019] [Indexed: 12/16/2022]
Abstract
Notch plays a protumorigenic role in many cancers including prostate cancer (PCa). Global notch inhibition of multiple Notch family members using γ-secretase inhibitors has shown efficacy in suppressing PCa growth in murine models. However, global Notch inhibition is associated with marked toxicity due to the widespread function of many different Notch family members in normal cell physiology. Accordingly, in the current study, we explored if specific inhibition of Notch1 would effectively inhibit PCa growth in a murine model. The androgen-dependent VCaP and androgen-independent DU145 cell lines were injected subcutaneously into mice. The mice were treated with either control antibody 1B7.11, anti-Notch1 antibody (OMP-A2G1), docetaxel or the combination of OMP-A2G1 and docetaxel. Tumor growth was measured using calipers. At the end of the study, tumors were assessed for proliferative response, apoptotic response, Notch target gene expression, and DNA damage response (DDR) expression. OMP-A2G1 alone inhibited tumor growth of both PCa cell lines to a greater extent than docetaxel alone. There was no additive or synergistic effect of OMP-A2G1 and docetaxel. The primary toxicity was weight loss that was controlled with dietary supplementation. Proliferation and apoptosis were affected differentially in the two cell lines. OMP-A2G1 increased expression of the DDR gene GADD45α in VCaP cells but downregulated GADD45α in Du145 cells. Taken together, these data show that Notch1 inhibition decreases PCa xenograft growth but does so through different mechanisms in the androgen-dependent VCaP cell line vs the androgen-independent DU145 cell line. These results provide a rationale for further exploration of targeted Notch inhibition for therapy of PCa.
Collapse
Affiliation(s)
- Aqila A Ahmed
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | - Tyler Robinson
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | - Monica Palande
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | | | - Jinlu Dai
- Department of Urology, University of Michigan, Ann Arbor, Michigan
| | - Evan T Keller
- Department of Urology, University of Michigan, Ann Arbor, Michigan.,Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
11
|
Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, Isse K, Kearney M, Vosoughi A, Fernandez L, Pan H, Motanagh S, Hess J, Donoghue AJ, Sboner A, Wang Y, Dittamore R, Rickman D, Nanus DM, Tagawa ST, Elemento O, Mosquera JM, Saunders L, Beltran H. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 2019; 11:eaav0891. [PMID: 30894499 PMCID: PMC6525633 DOI: 10.1126/scitranslmed.aav0891] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 02/11/2019] [Indexed: 01/06/2023]
Abstract
Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.
Collapse
MESH Headings
- Aged
- Animals
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Benzodiazepinones/pharmacology
- Benzodiazepinones/therapeutic use
- Carcinoma, Neuroendocrine/drug therapy
- Carcinoma, Neuroendocrine/genetics
- Carcinoma, Neuroendocrine/pathology
- Cell Line, Tumor
- Gene Expression Regulation, Neoplastic/drug effects
- Genetic Heterogeneity
- Humans
- Immunoconjugates/pharmacology
- Immunoconjugates/therapeutic use
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Molecular Targeted Therapy
- Neoplastic Cells, Circulating/metabolism
- Neoplastic Cells, Circulating/pathology
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/genetics
- Prostatic Neoplasms/pathology
- Prostatic Neoplasms, Castration-Resistant/drug therapy
- Prostatic Neoplasms, Castration-Resistant/genetics
- Prostatic Neoplasms, Castration-Resistant/pathology
- Time Factors
- Treatment Outcome
Collapse
Affiliation(s)
- Loredana Puca
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
| | - Katie Gavyert
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
| | - Verena Sailer
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Vincenza Conteduca
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, FC, Italy
| | - Etienne Dardenne
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Michael Sigouros
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Kumiko Isse
- AbbVie Stemcentrx LLC, South San Francisco, CA 94080, USA
| | | | - Aram Vosoughi
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | | | - Heng Pan
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
| | - Samaneh Motanagh
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Judy Hess
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Adam J Donoghue
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Andrea Sboner
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yuzhuo Wang
- University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | | | - David Rickman
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - David M Nanus
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
| | - Scott T Tagawa
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Juan Miguel Mosquera
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Laura Saunders
- AbbVie Stemcentrx LLC, South San Francisco, CA 94080, USA
| | - Himisha Beltran
- Division of Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork Presbyterian, New York, NY 10021, USA
- Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| |
Collapse
|
|
12
|
Neural Transcription Factors in Disease Progression. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1210:437-462. [PMID: 31900920 DOI: 10.1007/978-3-030-32656-2_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Progression to the malignant state is fundamentally dependent on transcriptional regulation in cancer cells. Optimum abundance of cell cycle proteins, angiogenesis factors, immune evasion markers, etc. is needed for proliferation, metastasis or resistance to treatment. Therefore, dysregulation of transcription factors can compromise the normal prostate transcriptional network and contribute to malignant disease progression.The androgen receptor (AR) is considered to be a key transcription factor in prostate cancer (PCa) development and progression. Consequently, androgen pathway inhibitors (APIs) are currently the mainstay in PCa treatment, especially in castration-resistant prostate cancer (CRPC). However, emerging evidence suggests that with increased administration of potent APIs, prostate cancer can progress to a highly aggressive disease that morphologically resembles small cell carcinoma, which is referred to as neuroendocrine prostate cancer (NEPC), treatment-induced or treatment-emergent small cell prostate cancer. This chapter will review how neuronal transcription factors play a part in inducing a plastic stage in prostate cancer cells that eventually progresses to a more aggressive state such as NEPC.
Collapse
|
|
13
|
Seok Y, Kang HG, Lee SY, Jeong JY, Choi JE, Jung DK, Jin CC, Hong MJ, Do SK, Lee WK, Park JY, Shin KM, Yoo SS, Lee J, Cho S, Cha SI, Kim CH, Jheon S, Lee EB, Park JY. Polymorphisms in Epithelial-Mesenchymal Transition-Related Genes and the Prognosis of Surgically Treated Non-small Cell Lung Cancer. Ann Surg Oncol 2017; 24:3386-3395. [PMID: 28766235 DOI: 10.1245/s10434-017-6002-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Indexed: 12/19/2022]
Abstract
BACKGROUND This study was conducted to determine whether single-nucleotide polymorphisms (SNPs) in EMT-related genes may influence the prognosis of NSCLC after surgery. METHODS There were 88 SNPs in EMT-related genes evaluated in a discovery set of 376 patients who underwent curative surgery for NSCLC. Significantly, 14 SNPs were evaluated in a validation set of 428 patients. Luciferase assay and RT-PCR were conducted to examine functional relevance of polymorphisms. RESULTS Fourteen SNPs that were associated with survival outcomes in a discovery set were selected for validation. Among those, two SNPs (FOXF2 rs1711972A>C and HEYL rs784621G>A) were replicated in a validation study. In combined analysis, FOXF2 rs1711972 AC+CC genotype was associated with significantly better overall survival (OS) and disease-free survival (DFS) compared with AA genotype (adjusted hazard ratio [aHR] for OS = 0.67, 95% confidence interval [CI] 0.51-0.88, P = 0.004; and aHR for DFS = 0.77, 95% CI 0.62-0.95, P = 0.01). HEYL rs784621 AA genotype exhibited a significantly worse OS compared with GG+GA genotype (aHR for OS = 2.65, 95% CI 1.63-4.31, P = 8 × 10-5). FOXF2 rs1711972C allele had a significantly increased promoter activity than rs1711972A allele (P = 0.01), and HEYL rs784621A allele had a significantly lower promoter activity than rs784621G allele (P = 0.004). FOXF2 rs1711972A>C was significantly associated with increased FOXF2 mRNA expression. CONCLUSIONS FOXF2 rs1711972A>C and HEYL rs784621G>A were associated with survival outcomes of surgically treated NSCLC. These SNPs may help to identify patients at high risk of poor disease outcomes.
Collapse
Affiliation(s)
- Yangki Seok
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.,Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Hyo-Gyoung Kang
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Shin Yup Lee
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ji Yun Jeong
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jin Eun Choi
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Deuk Kju Jung
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Cheng Cheng Jin
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Mi Jeong Hong
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Sook Kyung Do
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Won Kee Lee
- Biostatistics Medical Research Collaboration Center, Kyungpook National University Hospital and Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Ji Young Park
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kyung Min Shin
- Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Seung Soo Yoo
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jaehee Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sukki Cho
- Department of Thoracic and Cardiovascular Surgery, Seoul National University School of Medicine, Seoul, Republic of Korea
| | - Seung Ick Cha
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Chang Ho Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sanghoon Jheon
- Department of Thoracic and Cardiovascular Surgery, Seoul National University School of Medicine, Seoul, Republic of Korea
| | - Eung Bae Lee
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea. .,Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
| | - Jae Yong Park
- Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea. .,Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. .,Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. .,Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. .,BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea.
| |
Collapse
|
|
14
|
Liu Z, Sanders AJ, Liang G, Song E, Jiang WG, Gong C. Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment. Mol Cancer Ther 2017; 16:775-786. [PMID: 28468863 DOI: 10.1158/1535-7163.mct-16-0576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 12/29/2016] [Accepted: 12/29/2016] [Indexed: 11/16/2022]
Affiliation(s)
- Zihao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Andrew J Sanders
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| | - Gehao Liang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wen G Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
| | - Chang Gong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetic and Gene Regulation, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom
| |
Collapse
|
|
15
|
Kwon OJ, Zhang L, Wang J, Su Q, Feng Q, Zhang XHF, Mani SA, Paulter R, Creighton CJ, Ittmann MM, Xin L. Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J Clin Invest 2016; 126:2626-41. [PMID: 27294523 DOI: 10.1172/jci84637] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/22/2016] [Indexed: 12/28/2022] Open
Abstract
Although Notch signaling is deregulated in prostate cancer, the role of this pathway in disease development and progression is not fully understood. Here, we analyzed 2 human prostate cancer data sets and found that higher Notch signaling correlates with increased metastatic potential and worse disease survival rates. We used the Pten-null mouse prostate cancer model to investigate the function of Notch signaling in the initiation and progression of prostate cancer. Disruption of the transcription factor RBPJ in Pten-null mice revealed that endogenous canonical Notch signaling is not required for disease initiation and progression. However, augmentation of Notch activity in this model promoted both proliferation and apoptosis of prostate epithelial cells, which collectively reduced the primary tumor burden. The increase in cellular apoptosis was linked to DNA damage-induced p53 activation. Despite a reduced primary tumor burden, Notch activation in Pten-null mice promoted epithelial-mesenchymal transition and FOXC2-dependent tumor metastases but did not confer resistance to androgen deprivation. Notch activation also resulted in transformation of seminal vesicle epithelial cells in Pten-null mice. Our study highlights a multifaceted role for Notch signaling in distinct aspects of prostate cancer biology and supports Notch as a potential therapeutic target for metastatic prostate cancer.
Collapse
|
|
16
|
HEY1 functions are regulated by its phosphorylation at Ser-68. Biosci Rep 2016; 36:BSR20160123. [PMID: 27129302 PMCID: PMC5293587 DOI: 10.1042/bsr20160123] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 04/27/2016] [Indexed: 01/25/2023] Open
Abstract
HEY1-dependent activation of the p53 tumour suppressor pathway can be inhibited through direct phosphorylation of HEY1 at Ser-68 located in the bHLH domain. STK38 and STK38L serine/threonine kinases can phosphorylate HEY1 Ser-68 and could modulate its biological function. HEY1 (hairy/enhancer-of-split related with YRPW motif 1) is a member of the basic helix–loop–helix-orange (bHLH-O) family of transcription repressors that mediate Notch signalling. HEY1 acts as a positive regulator of the tumour suppressor p53 via still unknown mechanisms. A MALDI-TOF/TOF MS analysis has uncovered a novel HEY1 regulatory phosphorylation event at Ser-68. Strikingly, this single phosphorylation event controls HEY1 stability and function: simulation of HEY1 Ser-68 phosphorylation increases HEY1 protein stability but inhibits its ability to enhance p53 transcriptional activity. Unlike wild-type HEY1, expression of the phosphomimetic mutant HEY1-S68D failed to induce p53-dependent cell cycle arrest and it did not sensitize U2OS cells to p53-activating chemotherapeutic drugs. We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68. HEY1 is phosphorylated at Ser-68 during mitosis and it accumulates in the centrosomes of mitotic cells, suggesting a possible integration of HEY1-dependent signalling in centrosome function. Moreover, HEY1 interacts with a subset of p53-activating ribosomal proteins. Ribosomal stress causes HEY1 relocalization from the nucleoplasm to perinucleolar structures termed nucleolar caps. HEY1 interacts physically with at least one of the ribosomal proteins, RPL11, and both proteins cooperate in the inhibition of MDM2-mediated p53 degradation resulting in a synergistic positive effect on p53 transcriptional activity. HEY1 itself also interacts directly with MDM2 and it is subjected to MDM2-mediated degradation. Simulation of HEY1 Ser-68 phosphorylation prevents its interaction with p53, RPL11 and MDM2 and abolishes HEY1 migration to nucleolar caps upon ribosomal stress. Our findings uncover a novel mechanism for cross-talk between Notch signalling and nucleolar stress.
Collapse
|
|
17
|
Tesikova M, Dezitter X, Nenseth HZ, Klokk TI, Mueller F, Hager GL, Saatcioglu F. Divergent Binding and Transactivation by Two Related Steroid Receptors at the Same Response Element. J Biol Chem 2016; 291:11899-910. [PMID: 27056330 DOI: 10.1074/jbc.m115.684480] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Indexed: 01/19/2023] Open
Abstract
Transcription factor (TF) recruitment to chromatin is central to activation of transcription. TF-chromatin interactions are highly dynamic, which are evaluated by recovery half time (t1/2) in seconds, determined by fluorescence recovery experiments in living cells, and chromatin immunoprecipitation (ChIP) analysis, measured in minutes. These two states are related: the larger the t1/2, the longer the ChIP occupancy resulting in increased transcription. Here we present data showing that this relationship does not always hold. We found that histone deacetylase inhibitors (HDACis) significantly increased t1/2 of green fluorescent protein (GFP) fused androgen receptor (AR) on a tandem array of positive hormone response elements (HREs) in chromatin. This resulted in increased ChIP signal of GFP-AR. Unexpectedly, however, transcription was inhibited. In contrast, the GFP-fused glucocorticoid receptor (GR), acting through the same HREs, displayed a profile consistent with current models. We provide evidence that these differences are mediated, at least in part, by HDACs. Our results provide insight into TF action in living cells and show that very closely related TFs may trigger significantly divergent outcomes at the same REs.
Collapse
Affiliation(s)
- Martina Tesikova
- From the Department of Biosciences, University of Oslo, 0316 Oslo, Norway
| | - Xavier Dezitter
- From the Department of Biosciences, University of Oslo, 0316 Oslo, Norway
| | - Hatice Z Nenseth
- From the Department of Biosciences, University of Oslo, 0316 Oslo, Norway
| | - Tove I Klokk
- From the Department of Biosciences, University of Oslo, 0316 Oslo, Norway
| | - Florian Mueller
- Computational Imaging and Modeling Unit, Institut Pasteur, 75015 Paris, France
| | - Gordon L Hager
- Laboratory of Receptor Biology and Gene Expression, NCI, National Institutes of Health, Bethesda, Maryland 20892, and
| | - Fahri Saatcioglu
- From the Department of Biosciences, University of Oslo, 0316 Oslo, Norway, Institute for Cancer Genetics and Informatics, Division of Cancer and Surgery, Oslo University Hospital, 0310 Oslo, Norway
| |
Collapse
|
|
18
|
Deng G, Ma L, Meng Q, Ju X, Jiang K, Jiang P, Yu Z. Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology. J Cancer Res Clin Oncol 2016; 142:531-47. [PMID: 25736982 DOI: 10.1007/s00432-015-1946-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/22/2015] [Indexed: 01/08/2023]
Abstract
PURPOSE This review aims to summarize the evidence that Notch signaling is associated with prostate development, tumorigenesis and prostate tumor progression. METHODS Studies in PubMed database were searched using the keywords of Notch signaling, prostate development and prostate cancer. Relevant literatures were identified and summarized. RESULTS The Notch pathway plays an important role in determining cell fate, proliferation, differentiation and apoptosis. Recent findings have highlighted the involvement of Notch signaling in prostate development and in the maintenance of adult prostate homeostasis. Aberrant Notch expression in tissues leads to dysregulation of Notch functions and promotes various neoplasms, including prostate cancer. High expression of Notch has been implicated in prostate cancer, and its expression increases with higher cancer grade. However, the precise role of Notch in prostate cancer has yet to be clearly defined. The roles of Notch either as an oncogene or tumor suppressor in prostate cancer hallmarks such as cell proliferation, apoptosis and anoikis, hypoxia, migration and invasion, angiogenesis as well as the correlation with metastasis are therefore discussed. CONCLUSIONS Notch signaling is a complicated signaling pathway in modulating prostate development and prostate cancer. Understanding and manipulating Notch signaling could therefore be of potential therapeutic value in combating prostate cancer.
Collapse
Affiliation(s)
- Gang Deng
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| | - Libin Ma
- Department of Nephrology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China.
| | - Qi Meng
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| | - Xiang Ju
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| | - Kang Jiang
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| | - Peiwu Jiang
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| | - Zhijian Yu
- Department of Urology, The First People's Hospital of Hangzhou, 216 Huansha Road, Hangzhou, 310006, Zhejiang, China
| |
Collapse
|
|
19
|
Su Q, Xin L. Notch signaling in prostate cancer: refining a therapeutic opportunity. Histol Histopathol 2016; 31:149-57. [PMID: 26521657 PMCID: PMC4822406 DOI: 10.14670/hh-11-685] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Notch is an evolutionarily conserved signaling pathway that plays a critical role in specifying cell fate and regulating tissue homeostasis and carcinogenesis. Studies using organ cultures and genetically engineered mouse models have demonstrated that Notch signaling regulates prostate development and homeostasis. However, the role of the Notch signaling pathway in prostate cancer remains inconclusive. Many published studies have documented consistent deregulation of major Notch signaling components in human prostate cancer cell lines, mouse models for prostate cancers, and human prostate cancer specimens at both the mRNA and the protein levels. However, functional studies in human cancer cells by modulation of Notch pathway elements suggest both tumor suppressive and oncogenic roles of Notch. These controversies may originate from our inadequate understanding of the regulation of Notch signaling under versatile genetic contexts, and reflect the multifaceted and pleiotropic roles of Notch in regulating different aspects of prostate cancer cell biology, such as proliferation, metastasis, and chemo-resistance. Future comprehensive studies using various mouse models for prostate cancer may help clarify the role of Notch signaling in prostate cancer and provide a solid basis for determining whether and how Notch should be employed as a therapeutic target for prostate cancer.
Collapse
Affiliation(s)
- Qingtai Su
- Department of Molecular and Cellular Biology, Baylor College of Medicine, and Graduate Program in Integrative Molecular and Biomedical Sciences, Houston, Texas, USA
| | - Li Xin
- Department of Molecular and Cellular Biology, Department of Pathology and Immunology and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
|
20
|
Kwon OJ, Zhang L, Xin L. Stem Cell Antigen-1 Identifies a Distinct Androgen-Independent Murine Prostatic Luminal Cell Lineage with Bipotent Potential. Stem Cells 2015; 34:191-202. [PMID: 26418304 DOI: 10.1002/stem.2217] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 08/24/2015] [Indexed: 01/08/2023]
Abstract
Recent lineage tracing studies support the existence of prostate luminal progenitors that possess extensive regenerative capacity, but their identity remains unknown. We show that Sca-1 (stem cell antigen-1) identifies a small population of murine prostate luminal cells that reside in the proximal prostatic ducts adjacent to the urethra. Sca-1(+) luminal cells do not express Nkx3.1. They do not carry the secretory function, although they express the androgen receptor. These cells are enriched in the prostates of castrated mice. In the in vitro prostate organoid assay, a small fraction of the Sca-1(+) luminal cells are capable of generating budding organoids that are morphologically distinct from those derived from other cell lineages. Histologically, this type of organoid is composed of multiple inner layers of luminal cells surrounded by multiple outer layers of basal cells. When passaged, these organoids retain their morphological and histological features. Finally, the Sca-1(+) luminal cells are capable of forming small prostate glands containing both basal and luminal cells in an in vivo prostate regeneration assay. Collectively, our study establishes the androgen-independent and bipotent organoid-forming Sca-1(+) luminal cells as a functionally distinct cellular entity. These cells may represent a putative luminal progenitor population and serve as a cellular origin for castration resistant prostate cancer.
Collapse
Affiliation(s)
- Oh-Joon Kwon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Li Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Li Xin
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.,Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
| |
Collapse
|
|
21
|
Kuo KK, Jian SF, Li YJ, Wan SW, Weng CC, Fang K, Wu DC, Cheng KH. Epigenetic inactivation of transforming growth factor-β1 target gene HEYL, a novel tumor suppressor, is involved in the P53-induced apoptotic pathway in hepatocellular carcinoma. Hepatol Res 2015; 45:782-93. [PMID: 25179429 DOI: 10.1111/hepr.12414] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Revised: 08/26/2014] [Accepted: 08/27/2014] [Indexed: 02/08/2023]
Abstract
AIM Hairy/enhancer-of-split related with YRPW motif-like (HEYL) protein was first identified as a transcriptional repressor. It is a downstream gene of the Notch and transforming growth factor-β pathways. Little is known about its role in the pathogenesis of hepatocellular carcinoma (HCC). METHODS Eighty surgically resected paired HCC and adjacent non-cancerous tissues were analyzed for HEYL expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). HCC cells were transfected with pHEYL-EGFP vector to overexpress the HEYL gene or infected with specific shHEYL lentiviral vector to silence HEYL gene expression. HEYL expressional analysis and functional characterization were assessed by 3-(4 5-dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays, flow cytometry, RT-qPCR, western blotting and methylation-specific PCR. RESULTS We determined that HEYL expression was inactivated in more than 75% of HCC. In addition, overexpression of HEYL in SK-Hep 1 cells caused apoptosis by the cleavage of caspase 3 and poly (ADP-ribose) polymerase. We discovered that HEYL apoptosis was preceded by serine 15 phosphorylation and accumulation of P53. Molecular analysis revealed that HEYL overexpression led to increased p16, p19, p21, p27 and Bad protein expression, and reduced c-Myc, Bcl-2 and Cyclin B1 expression. Epigenetic silencing of HEYL expression by DNA hypermethylation in HCC directly correlated with loss of HEYL expression in HCC. CONCLUSION HEYL is frequently downregulated by promoter methylation in HCC. HEYL may be a tumor suppressor of liver carcinogenesis through upregulation of P53 gene expression and activation of P53-mediated apoptosis.
Collapse
Affiliation(s)
- Kung-Kai Kuo
- Department of Surgery, Division of Hepatobiliary Pancreatic Surgery, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Fang Jian
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yi-Jin Li
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Shi-Wei Wan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Ching-Chieh Weng
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - KuanTe Fang
- Department of Research and Development, Eternal Chemical, Kaohsiung, Taiwan
| | - Deng-Chyang Wu
- Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Kuang-Hung Cheng
- Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| |
Collapse
|
|
22
|
Hey bHLH Proteins Interact with a FBXO45 Containing SCF Ubiquitin Ligase Complex and Induce Its Translocation into the Nucleus. PLoS One 2015; 10:e0130288. [PMID: 26068074 PMCID: PMC4466309 DOI: 10.1371/journal.pone.0130288] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 05/18/2015] [Indexed: 02/02/2023] Open
Abstract
The Hey protein family, comprising Hey1, Hey2 and HeyL in mammals, conveys Notch signals in many cell types. The helix-loop-helix (HLH) domain as well as the Orange domain, mediate homo- and heterodimerization of these transcription factors. Although distinct interaction partners have been identified so far, their physiological relevance for Hey functions is still largely unclear. Using a tandem affinity purification approach and mass spectrometry analysis we identified members of an ubiquitin E3-ligase complex consisting of FBXO45, PAM and SKP1 as novel Hey1 associated proteins. There is a direct interaction between Hey1 and FBXO45, whereas FBXO45 is needed to mediate indirect Hey1 binding to SKP1. Expression of Hey1 induces translocation of FBXO45 and PAM into the nucleus. Hey1 is a short-lived protein that is degraded by the proteasome, but there is no evidence for FBXO45-dependent ubiquitination of Hey1. On the contrary, Hey1 mediated nuclear translocation of FBXO45 and its associated ubiquitin ligase complex may extend its spectrum to additional nuclear targets triggering their ubiquitination. This suggests a novel mechanism of action for Hey bHLH factors.
Collapse
|
|
23
|
Brooke GN, Powell SM, Lavery DN, Waxman J, Buluwela L, Ali S, Bevan CL. Engineered repressors are potent inhibitors of androgen receptor activity. Oncotarget 2015; 5:959-69. [PMID: 24659630 PMCID: PMC4011597 DOI: 10.18632/oncotarget.1360] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These ‘engineered repressors’ are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.
Collapse
Affiliation(s)
- Greg N Brooke
- Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, W12 0NN, UK
| | | | | | | | | | | | | |
Collapse
|
|
24
|
Sriram R, Lo V, Pryce B, Antonova L, Mears AJ, Daneshmand M, McKay B, Conway SJ, Muller WJ, Sabourin LA. Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity. Breast Cancer Res 2015; 17:7. [PMID: 25592291 PMCID: PMC4355979 DOI: 10.1186/s13058-014-0513-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer. METHODS Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis. RESULTS Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn-null animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn-null environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15). CONCLUSIONS Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.
Collapse
Affiliation(s)
- Roshan Sriram
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
| | - Vivian Lo
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
| | - Benjamin Pryce
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
| | - Lilia Antonova
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
| | - Alan J Mears
- Children's Hospital of Eastern Ontario, Research Institute, 501 Smyth Road, Ottawa, ON, K1H8L6, Canada.
| | - Manijeh Daneshmand
- Ottawa Hospital Research Institute, Cancer Therapeutics, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.
| | - Bruce McKay
- Department of Biology and Institute of Biochemistry, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
| | - Simon J Conway
- Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, 705 Riley Hospital Drive, Indianapolis, IN, 46202, USA.
| | - William J Muller
- Department of Biochemistry and Goodman Cancer Research Center, McGill University, 1200 Pine Avenue West, Montreal, QC, H3G 1A1, Canada.
| | - Luc A Sabourin
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. .,Ottawa Hospital Research Institute, Cancer Therapeutics, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.
| |
Collapse
|
|
25
|
Felgueiras J, Fardilha M. Phosphoprotein phosphatase 1-interacting proteins as therapeutic targets in prostate cancer. World J Pharmacol 2014; 3:120-139. [DOI: 10.5497/wjp.v3.i4.120] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 09/01/2014] [Accepted: 09/24/2014] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer is a major public health concern worldwide, being one of the most prevalent cancers in men. Great improvements have been made both in terms of early diagnosis and therapeutics. However, there is still an urgent need for reliable biomarkers that could overcome the lack of cancer-specificity of prostate-specific antigen, as well as alternative therapeutic targets for advanced metastatic cases. Reversible phosphorylation of proteins is a post-translational modification critical to the regulation of numerous cellular processes. Phosphoprotein phosphatase 1 (PPP1) is a major serine/threonine phosphatase, whose specificity is determined by its interacting proteins. These interactors can be PPP1 substrates, regulators, or even both. Deregulation of this protein-protein interaction network alters cell dynamics and underlies the development of several cancer hallmarks. Therefore, the identification of PPP1 interactome in specific cellular context is of crucial importance. The knowledge on PPP1 complexes in prostate cancer remains scarce, with only 4 holoenzymes characterized in human prostate cancer models. However, an increasing number of PPP1 interactors have been identified as expressed in human prostate tissue, including the tumor suppressors TP53 and RB1. Efforts should be made in order to identify the role of such proteins in prostate carcinogenesis, since only 26 have yet well-recognized roles. Here, we revise literature and human protein databases to provide an in-depth knowledge on the biological significance of PPP1 complexes in human prostate carcinogenesis and their potential use as therapeutic targets for the development of new therapies for prostate cancer.
Collapse
|
|
26
|
Jingushi K, Ueda Y, Kitae K, Hase H, Egawa H, Ohshio I, Kawakami R, Kashiwagi Y, Tsukada Y, Kobayashi T, Nakata W, Fujita K, Uemura M, Nonomura N, Tsujikawa K. miR-629 Targets TRIM33 to Promote TGFβ/Smad Signaling and Metastatic Phenotypes in ccRCC. Mol Cancer Res 2014; 13:565-74. [PMID: 25381221 DOI: 10.1158/1541-7786.mcr-14-0300] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and clear cell RCC (ccRCC) represents its most common histological subtype. To identify a therapeutic target for ccRCC, miRNA expression signatures from ccRCC clinical specimens were analyzed. miRNA microarray and real-time PCR analyses revealed that miR-629 expression was significantly upregulated in human ccRCC compared with adjacent noncancerous renal tissue. Functional inhibition of miR-629 by a hairpin miRNA inhibitor suppressed ccRCC cell motility and invasion. Mechanistically, miR-629 directly targeted tripartite motif-containing 33 (TRIM33), which inhibits the TGFβ/Smad signaling pathway. In clinical ccRCC specimens, downregulation of TRIM33 was observed with the association of both pathologic stages and grades. The miR-629 inhibitor significantly suppressed TGFβ-induced Smad activation by upregulating TRIM33 expression and subsequently inhibited the association of Smad2/3 and Smad4. Moreover, a miR-629 mimic enhanced the effect of TGFβ on the expression of epithelial-mesenchymal transition-related factors as well as on the motility and invasion in ccRCC cells. These findings identify miR-629 as a potent regulator of the TGFβ/Smad signaling pathway via TRIM33 in ccRCC. IMPLICATIONS This study suggests that miR-629 has biomarker potential through its ability to regulate TGFβ/Smad signaling and accelerate ccRCC cell motility and invasion.
Collapse
Affiliation(s)
- Kentaro Jingushi
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
| | - Yuko Ueda
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Kaori Kitae
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Hiroaki Hase
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Hiroshi Egawa
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Ikumi Ohshio
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Ryoji Kawakami
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Yuri Kashiwagi
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Yohei Tsukada
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Takumi Kobayashi
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Wataru Nakata
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazutoshi Fujita
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Motohide Uemura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Norio Nonomura
- Department of Urology, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazutake Tsujikawa
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| |
Collapse
|
|
27
|
Wigglesworth K, Lee KB, Emori C, Sugiura K, Eppig JJ. Transcriptomic diversification of developing cumulus and mural granulosa cells in mouse ovarian follicles. Biol Reprod 2014; 92:23. [PMID: 25376232 DOI: 10.1095/biolreprod.114.121756] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cumulus cells and mural granulosa cells (MGCs) have functionally distinct roles in antral follicles, and comparison of their transcriptomes at a global and systems level can propel future studies on mechanisms underlying their functional diversity. These cells were isolated from small and large antral follicles before and after stimulation of immature mice with gonadotropins, respectively. Both cell types underwent dramatic transcriptomic changes, and differences between them increased with follicular growth. Although cumulus cells of both stages of follicular development are competent to undergo expansion in vitro, they were otherwise remarkably dissimilar with transcriptomic changes quantitatively equivalent to those of MGCs. Gene ontology analysis revealed that cumulus cells of small follicles were enriched in transcripts generally associated with catalytic components of metabolic processes, while those from large follicles were involved in regulation of metabolism, cell differentiation, and adhesion. Contrast of cumulus cells versus MGCs revealed that cumulus cells were enriched in transcripts associated with metabolism and cell proliferation while MGCs were enriched for transcripts involved in cell signaling and differentiation. In vitro and in vivo models were used to test the hypothesis that higher levels of transcripts in cumulus cells versus MGCs is the result of stimulation by oocyte-derived paracrine factors (ODPFs). Surprisingly ∼48% of transcripts higher in cumulus cells than MGCs were not stimulated by ODPFs. Those stimulated by ODPFs were mainly associated with cell division, mRNA processing, or the catalytic pathways of metabolism, while those not stimulated by ODPFs were associated with regulatory processes such as signaling, transcription, phosphorylation, or the regulation of metabolism.
Collapse
Affiliation(s)
| | - Kyung-Bon Lee
- Department of Biology Education, College of Education, Chonnam National University, Buk-gu, Gwangju, Korea
| | - Chihiro Emori
- Laboratory of Applied Genetics, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Koji Sugiura
- Laboratory of Applied Genetics, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | | |
Collapse
|
|
28
|
Abstract
While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.
Collapse
Affiliation(s)
- Gerard A Tarulli
- Dame Roma Mitchell Cancer Research Laboratories (DRMCRL)Faculty of Health Sciences, School of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Lisa M Butler
- Dame Roma Mitchell Cancer Research Laboratories (DRMCRL)Faculty of Health Sciences, School of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Wayne D Tilley
- Dame Roma Mitchell Cancer Research Laboratories (DRMCRL)Faculty of Health Sciences, School of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia
| | - Theresa E Hickey
- Dame Roma Mitchell Cancer Research Laboratories (DRMCRL)Faculty of Health Sciences, School of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia
| |
Collapse
|
|
29
|
Kwon OJ, Valdez J, Zhang L, Zhang B, Wei X, Su Q, Ittmann MM, Creighton CJ, Xin L. Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat Commun 2014; 5:4416. [PMID: 25048699 PMCID: PMC4167399 DOI: 10.1038/ncomms5416] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 06/16/2014] [Indexed: 02/07/2023] Open
Abstract
The prostate epithelial lineage hierarchy remains inadequately defined. Recent lineage-tracing studies have implied the existence of prostate luminal epithelial progenitors with extensive regenerative capacity. However, this capacity has not been demonstrated in prostate stem cell activity assays, probably owing to the strong susceptibility of luminal progenitors to anoikis. Here we show that constitutive expression of Notch1 intracellular domain impairs secretory function of mouse prostate luminal cells, suppresses anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes1, stimulates luminal cell proliferation by potentiating PI3K-AKT signalling, and rescues the capacities of the putative prostate luminal progenitors for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell autonomous AR signalling is dispensable for the Notch-mediated effects. As Notch activity is increased in prostate cancers, and anoikis resistance is a hallmark for metastatic cancer cells, this study suggests a pro-metastatic function of Notch signalling during prostate cancer progression.
Collapse
Affiliation(s)
- Oh-Joon Kwon
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Joseph Valdez
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Li Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Boyu Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Xing Wei
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Qingtai Su
- Department of Molecular and Cellular Biology, Baylor College of Medicine
| | - Michael M Ittmann
- Department of Pathology and Immunology, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
- Michael E. DeBakey Department of Veterans Affairs Medical Center
| | | | - Li Xin
- Department of Molecular and Cellular Biology, Baylor College of Medicine
- Department of Pathology and Immunology, Baylor College of Medicine
- Dan L. Duncan Cancer Center, Baylor College of Medicine
| |
Collapse
|
|
30
|
Abstract
Hey bHLH transcription factors are direct targets of canonical Notch signaling. The three mammalian Hey proteins are closely related to Hes proteins and they primarily repress target genes by either directly binding to core promoters or by inhibiting other transcriptional activators. Individual candidate gene approaches and systematic screens identified a number of Hey target genes, which often encode other transcription factors involved in various developmental processes. Here, we review data on interaction partners and target genes and conclude with a model for Hey target gene regulation. Furthermore, we discuss how expression of Hey proteins affects processes like cell fate decisions and differentiation, e.g., in cardiovascular, skeletal, and neural development or oncogenesis and how this relates to the observed developmental defects and phenotypes observed in various knockout mice.
Collapse
Affiliation(s)
- David Weber
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany
| | - Cornelia Wiese
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany
| | - Manfred Gessler
- Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Wuerzburg University, Wuerzburg, Germany; Comprehensive Cancer Center Mainfranken, Wuerzburg University, Wuerzburg, Germany.
| |
Collapse
|
|
31
|
Frank SB, Miranti CK. Disruption of prostate epithelial differentiation pathways and prostate cancer development. Front Oncol 2013; 3:273. [PMID: 24199173 PMCID: PMC3813973 DOI: 10.3389/fonc.2013.00273] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Accepted: 10/18/2013] [Indexed: 12/14/2022] Open
Abstract
One of the foremost problems in the prostate cancer (PCa) field is the inability to distinguish aggressive from indolent disease, which leads to difficult prognoses and thousands of unnecessary surgeries. This limitation stems from the fact that the mechanisms of tumorigenesis in the prostate are poorly understood. Some genetic alterations are commonly reported in prostate tumors, including upregulation of Myc, fusion of Ets genes to androgen-regulated promoters, and loss of Pten. However, the specific roles of these aberrations in tumor initiation and progression are poorly understood. Likewise, the cell of origin for PCa remains controversial and may be linked to the aggressive potential of the tumor. One important clue is that prostate tumors co-express basal and luminal protein markers that are restricted to their distinct cell types in normal tissue. Prostate epithelium contains layer-specific stem cells as well as rare bipotent cells, which can differentiate into basal or luminal cells. We hypothesize that the primary oncogenic cell of origin is a transient-differentiating bipotent cell. Such a cell must maintain tight temporal and spatial control of differentiation pathways, thus increasing its susceptibility for oncogenic disruption. In support of this hypothesis, many of the pathways known to be involved in prostate differentiation can be linked to genes commonly altered in PCa. In this article, we review what is known about important differentiation pathways (Myc, p38MAPK, Notch, PI3K/Pten) in the prostate and how their misregulation could lead to oncogenesis. Better understanding of normal differentiation will offer new insights into tumor initiation and may help explain the functional significance of common genetic alterations seen in PCa. Additionally, this understanding could lead to new methods for classifying prostate tumors based on their differentiation status and may aid in identifying more aggressive tumors.
Collapse
Affiliation(s)
- Sander B Frank
- Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute , Grand Rapids, MI , USA ; Genetics Graduate Program, Michigan State University , East Lansing, MI , USA
| | | |
Collapse
|
|
32
|
Bjerrum JT, Rantalainen M, Wang Y, Olsen J, Nielsen OH. Integration of transcriptomics and metabonomics: improving diagnostics, biomarker identification and phenotyping in ulcerative colitis. Metabolomics 2013; 10:280-290. [PMID: 25221466 PMCID: PMC4161940 DOI: 10.1007/s11306-013-0580-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 08/10/2013] [Indexed: 12/18/2022]
Abstract
A systems biology approach to multi-faceted diseases has provided an opportunity to establish a holistic understanding of the processes at play. Thus, the current study merges transcriptomics and metabonomics data in order to improve diagnostics, biomarker identification and to explore the possibilities of a molecular phenotyping of ulcerative colitis (UC) patients. Biopsies were obtained from the descending colon of 43 UC patients (22 active UC and 21 quiescent UC) and 15 controls. Genome-wide gene expression analyses were performed using Affymetrix GeneChip Human Genome U133 Plus 2.0. Metabolic profiles were generated using 1H Nuclear magnetic resonance spectroscopy (Bruker 600 MHz, Bruker BioSpin, Rheinstetten, Germany). Data were analyzed with the use of orthogonal-projection to latent structure-discriminant analysis and a multivariate logistic regression model fitted by lasso. Prediction performance was evaluated using nested Monte Carlo cross-validation. The prediction performance of the merged data sets and that of relative small (<20 variables) multivariate biomarker panels suggest that it is possible to discriminate between active UC, quiescent UC, and controls; between patients with or without steroid dependency, as well as between early or late disease onset. Consequently, this study demonstrates that the novel approach of integrating metabonomics and transcriptomics combines the better of the two worlds, and provides us with clinical applicable candidate biomarker panels. These combined panels improve diagnostics and more importantly also the molecular phenotyping in UC and provide insight into the pathophysiological processes at play, making optimized and personalized medication a possibility.
Collapse
Affiliation(s)
- Jacob Tveiten Bjerrum
- Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Mattias Rantalainen
- Department of Statistics, Oxford University, Oxford, UK
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, People’s Republic of China
| | - Yulan Wang
- State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, People’s Republic of China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, People’s Republic of China
| | - Jørgen Olsen
- Department of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
33
|
Cano LQ, Lavery DN, Bevan CL. Mini-review: Foldosome regulation of androgen receptor action in prostate cancer. Mol Cell Endocrinol 2013; 369:52-62. [PMID: 23395916 DOI: 10.1016/j.mce.2013.01.023] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 01/28/2013] [Accepted: 01/29/2013] [Indexed: 11/24/2022]
Abstract
Steroid hormone receptors play diverse roles in many aspects of human physiology including cell division, apoptosis and homeostasis, tissue differentiation, sexual development and response to stress. These ligand-activated transcription factors require the functional activity of numerous chaperone and chaperone-associated proteins, collectively termed the foldosome, at the crucial step of ligand recognition and binding. Since the initial isolation of foldosome components and pioneering research by Pratt, Toft and colleagues we understand much regarding cytosolic receptor function. The classical view, that the role of foldosome components is restricted to the cytosol, has been modified over recent years by research highlighting additional roles of chaperone proteins in nuclear translocation and target gene expression. Further, dysregulation of chaperone activity and expression has been implicated in various cancers, including breast and prostate cancer. Consequently, the foldosome provides an attractive therapeutic target in steroid hormone receptor-driven malignancies. This review summarises current knowledge of how the foldosome impacts upon androgen receptor signalling, which is the key therapeutic target on prostate cancer, and how foldosome components may be used as biomarkers or therapeutic targets in this disease.
Collapse
Affiliation(s)
- Laia Querol Cano
- Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom
| | | | | |
Collapse
|
|
34
|
Fayyaz S, Farooqi AA. miRNA and TMPRSS2-ERG do not mind their own business in prostate cancer cells. Immunogenetics 2013; 65:315-32. [DOI: 10.1007/s00251-012-0677-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2012] [Accepted: 12/25/2012] [Indexed: 12/19/2022]
|
|
35
|
One size fits all in prostate cancer: a story tale whose time has come and gone. Int J Biol Markers 2011; 26:75-81. [PMID: 21623584 DOI: 10.5301/jbm.2011.8368] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2011] [Indexed: 12/31/2022]
Abstract
The touchstone to evaluate accurately the aggressiveness and invasiveness of prostate cancer is something of a holy grail in the facet of urologic oncology. Gene expression and sequencing studies have improved our interpretations of the genetic determinants of the disease but are unsuccessful in the establishment of any unified classification to improve the molecular stratification. These questions addressing failure in rational drug design are difficult to answer in the multifaceted and heterogeneous pathogenesis of prostate cancer. In this review, we have developed a roadmap of the "recalcitrant prostate cancer proteome" to recognize the aspects of prostate cancer that may be helpful in effectively translating these findings to the clinic.
Collapse
|