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Baselious F, Hilscher S, Hagemann S, Tripathee S, Robaa D, Barinka C, Hüttelmaier S, Schutkowski M, Sippl W. Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity. Arch Pharm (Weinheim) 2024; 357:e2400486. [PMID: 38996352 DOI: 10.1002/ardp.202400486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/14/2024]
Abstract
AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 µM on neuroblastoma cells.
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Affiliation(s)
- Fady Baselious
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Sebastian Hilscher
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Sven Hagemann
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Sunita Tripathee
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dina Robaa
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Cyril Barinka
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Vestec, Czech Republic
| | - Stefan Hüttelmaier
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Mike Schutkowski
- Charles Tanford Protein Center, Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
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Hashemi Karoii D, Bavandi S, Djamali M, Abroudi AS. Exploring the interaction between immune cells in the prostate cancer microenvironment combining weighted correlation gene network analysis and single-cell sequencing: An integrated bioinformatics analysis. Discov Oncol 2024; 15:513. [PMID: 39349877 PMCID: PMC11442730 DOI: 10.1007/s12672-024-01399-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/25/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND The rise of treatment resistance and variability across malignant profiles has made precision oncology an imperative in today's medical landscape. Prostate cancer is a prevalent form of cancer in males, characterized by significant diversity in both genomic and clinical characteristics. The tumor microenvironment consists of stroma, tumor cells, and various immune cells. The stromal components and tumor cells engage in mutual communication and facilitate the development of a low-oxygen and pro-cancer milieu by producing cytokines and activating pro-inflammatory signaling pathways. METHODS In order to discover new genes associated with tumor cells that interact and facilitate a hypoxic environment in prostate cancer, we conducted a cutting-edge bioinformatics investigation. This included analyzing high-throughput genomic datasets obtained from the cancer genome atlas (TCGA). RESULTS A combination of weighted gene co-expression network analysis and single-cell sequencing has identified nine dysregulated immune hub genes (AMACR, KCNN3, MME, EGFR, FLT1, GDF15, KDR, IGF1, and KRT7) that are believed to have significant involvement in the biological pathways involved with the advancement of prostate cancer enviriment. In the prostate cancer environment, we observed the overexpression of GDF15 and KRT7 genes, as well as the downregulation of other genes. Additionally, the cBioPortal platform was used to investigate the frequency of alterations in the genes and their effects on the survival of the patients. The Kaplan-Meier survival analysis indicated that the changes in the candidate genes were associated with a reduction in the overall survival of the patients. CONCLUSIONS In summary, the findings indicate that studying the genes and their genomic changes may be used to develop precise treatments for prostate cancer. This approach involves early detection and targeted therapy.
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Affiliation(s)
- Danial Hashemi Karoii
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
| | - Sobhan Bavandi
- Department of Biology, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
| | - Melika Djamali
- Department of Biology, Faculty of Science, Tehran University, Tehran, Iran
| | - Ali Shakeri Abroudi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Zhang Y, Liu Z, Yu L, Fan A, Li Y, Li X, Chen W. Integrative bioinformatics approach yields a novel gene expression risk model for prognosis and progression prediction in prostate cancer. J Cell Mol Med 2024; 28:e18405. [PMID: 38842134 PMCID: PMC11154836 DOI: 10.1111/jcmm.18405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/13/2024] [Accepted: 05/02/2024] [Indexed: 06/07/2024] Open
Abstract
Prostate cancer (PCa), a prevalent malignancy among elderly males, exhibits a notable rate of advancement, even when subjected to conventional androgen deprivation therapy or chemotherapy. An effective progression prediction model would prove invaluable in identifying patients with a higher progression risk. Using bioinformatics strategies, we integrated diverse data sets of PCa to construct a novel risk model predicated on gene expression and progression-free survival (PFS). The accuracy of the model was assessed through validation using an independent data set. Eight genes were discerned as independent prognostic factors and included in the prediction model. Patients assigned to the high-risk cohort demonstrated a diminished PFS, and the areas under the curve of our model in the validation set for 1-year, 3-year, and 5-year PFS were 0.9325, 0.9041 and 0.9070, respectively. Additionally, through the application of single-cell RNA sequencing to two castration-related prostate cancer (CRPC) samples and two hormone-related prostate cancer (HSPC) samples, we discovered that luminal cells within CRPC exhibited an elevated risk score. Subsequent molecular biology experiments corroborated our findings, illustrating heightened SYK expression levels within tumour tissues and its contribution to cancer cell migration. We found that the knockdown of SYK could inhibit migration in PCa cells. Our progression-related risk model demonstrated the potential prognostic value of SYK and indicated its potential as a target for future diagnosis and treatment strategies in PCa management.
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Affiliation(s)
- Yunyan Zhang
- Department of UrologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Zhuolin Liu
- School of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Liu Yu
- School of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Aoyu Fan
- Department of UrologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yunpeng Li
- Department of UrologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Xiaobo Li
- School of Basic Medical SciencesFudan UniversityShanghaiChina
| | - Wei Chen
- Department of UrologyZhongshan Hospital, Fudan UniversityShanghaiChina
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Kouchaki H, Kamyab P, Darbeheshti F, Gharezade A, Fouladseresht H, Tabrizi R. miR-939, as an important regulator in various cancers pathogenesis, has diagnostic, prognostic, and therapeutic values: a review. J Egypt Natl Canc Inst 2024; 36:16. [PMID: 38679648 DOI: 10.1186/s43046-024-00220-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 04/06/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND MicroRNAs (miRNAs or miRs) are highly conserved non-coding RNAs with a short length (18-24 nucleotides) that directly bind to a complementary sequence within 3'-untranslated regions of their target mRNAs and regulate gene expression, post-transcriptionally. They play crucial roles in diverse biological processes, including cell proliferation, apoptosis, and differentiation. In the context of cancer, miRNAs are key regulators of growth, angiogenesis, metastasis, and drug resistance. MAIN BODY This review primarily focuses on miR-939 and its expanding roles and target genes in cancer pathogenesis. It compiles findings from various investigations. MiRNAs, due to their dysregulated expression in tumor environments, hold potential as cancer biomarkers. Several studies have highlighted the dysregulation of miR-939 expression in human cancers. CONCLUSION Our study highlights the potential of miR-939 as a valuable target in cancer diagnosis, prognosis, and treatment. The aberrant expression of miR-939, along with other miRNAs, underscores their significance in advancing our understanding of cancer biology and their promise in personalized cancer care.
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Affiliation(s)
- Hosein Kouchaki
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parnia Kamyab
- USERN Office, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Darbeheshti
- Department of Radiation Oncology, Dana Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Arezou Gharezade
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamed Fouladseresht
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Reza Tabrizi
- Clinical Research Development Unit, Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran.
- Noncommunicable Diseases Research Center, Fasa University of Medical Science, Fasa, Iran.
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Baselious F, Hilscher S, Robaa D, Barinka C, Schutkowski M, Sippl W. Comparative Structure-Based Virtual Screening Utilizing Optimized AlphaFold Model Identifies Selective HDAC11 Inhibitor. Int J Mol Sci 2024; 25:1358. [PMID: 38279359 PMCID: PMC10816272 DOI: 10.3390/ijms25021358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/14/2024] [Accepted: 01/20/2024] [Indexed: 01/28/2024] Open
Abstract
HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine learning approach that can predict the 3D structure of proteins with high accuracy even in absence of similar structures. However, the fact that AlphaFold models are predicted in the absence of small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an HDAC11 AlphaFold model by adding the catalytic zinc ion and minimization in the presence of reported HDAC11 inhibitors. In the current study, we implement a comparative structure-based virtual screening approach utilizing the previously optimized HDAC11 AlphaFold model to identify novel and selective HDAC11 inhibitors. The stepwise virtual screening approach was successful in identifying a hit that was subsequently tested using an in vitro enzymatic assay. The hit compound showed an IC50 value of 3.5 µM for HDAC11 and could selectively inhibit HDAC11 over other HDAC subtypes at 10 µM concentration. In addition, we carried out molecular dynamics simulations to further confirm the binding hypothesis obtained by the docking study. These results reinforce the previously presented AlphaFold optimization approach and confirm the applicability of AlphaFold models in the search for novel inhibitors for drug discovery.
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Affiliation(s)
- Fady Baselious
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (F.B.); (S.H.); (D.R.)
| | - Sebastian Hilscher
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (F.B.); (S.H.); (D.R.)
| | - Dina Robaa
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (F.B.); (S.H.); (D.R.)
| | - Cyril Barinka
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, 252 50 Vestec, Czech Republic;
| | - Mike Schutkowski
- Charles Tanford Protein Center, Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany;
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany; (F.B.); (S.H.); (D.R.)
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Baselious F, Robaa D, Sippl W. Utilization of AlphaFold models for drug discovery: Feasibility and challenges. Histone deacetylase 11 as a case study. Comput Biol Med 2023; 167:107700. [PMID: 37972533 DOI: 10.1016/j.compbiomed.2023.107700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/19/2023]
Abstract
Histone deacetylase 11 (HDAC11), an enzyme that cleaves acyl groups from acylated lysine residues, is the sole member of class IV of HDAC family with no reported crystal structure so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms which complicates the conventional template-based homology modeling. AlphaFold is a neural network machine learning approach for predicting the 3D structures of proteins with atomic accuracy even in absence of similar structures. However, the structures predicted by AlphaFold are missing small molecules as ligands and cofactors. In our study, we first optimized the HDAC11 AlphaFold model by adding the catalytic zinc ion followed by assessment of the usability of the model by docking of the selective inhibitor FT895. Minimization of the optimized model in presence of transplanted inhibitors, which have been described as HDAC11 inhibitors, was performed. Four complexes were generated and proved to be stable using three replicas of 50 ns MD simulations and were successfully utilized for docking of the selective inhibitors FT895, MIR002 and SIS17. For SIS17, The most reasonable pose was selected based on structural comparison between HDAC6, HDAC8 and the HDAC11 optimized AlphaFold model. The manually optimized HDAC11 model is thus able to explain the binding behavior of known HDAC11 inhibitors and can be used for further structure-based optimization.
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Affiliation(s)
- Fady Baselious
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Dina Robaa
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany
| | - Wolfgang Sippl
- Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
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Liu Y, Tong X, Hu W, Chen D. HDAC11: A novel target for improved cancer therapy. Biomed Pharmacother 2023; 166:115418. [PMID: 37659201 DOI: 10.1016/j.biopha.2023.115418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023] Open
Abstract
Histone deacetylase 11 (HDAC11) is a unique member of the histone deacetylase family that plays an important role in the regulation of gene expression and protein function. In recent years, research on the role of HDAC11 in tumors has attracted increasing attention. This review summarizes the current knowledge on the subcellular localization, structure, expression, and functions of HDAC11 in tumors, as well as the regulatory mechanisms involved in its network, including ncRNA and substrates. Moreover, we focus on the progress made in targeting HDAC11 to overcome tumor therapy resistance, and the development of HDAC11 inhibitors for cancer treatment. Collectively, this review provides comprehensive insights into the potential clinical implications of HDAC11 for cancer therapy.
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Affiliation(s)
- Yan Liu
- First Department of Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China
| | - Xuechao Tong
- Department of Emergency, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China
| | - Weina Hu
- Department of General Practice, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China.
| | - Da Chen
- Department of Emergency, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China.
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Zhou S, Van Bortle K. The Pol III transcriptome: Basic features, recurrent patterns, and emerging roles in cancer. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1782. [PMID: 36754845 PMCID: PMC10498592 DOI: 10.1002/wrna.1782] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 01/13/2023] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
The RNA polymerase III (Pol III) transcriptome is universally comprised of short, highly structured noncoding RNA (ncRNA). Through RNA-protein interactions, the Pol III transcriptome actuates functional activities ranging from nuclear gene regulation (7SK), splicing (U6, U6atac), and RNA maturation and stability (RMRP, RPPH1, Y RNA), to cytoplasmic protein targeting (7SL) and translation (tRNA, 5S rRNA). In higher eukaryotes, the Pol III transcriptome has expanded to include additional, recently evolved ncRNA species that effectively broaden the footprint of Pol III transcription to additional cellular activities. Newly evolved ncRNAs function as riboregulators of autophagy (vault), immune signaling cascades (nc886), and translation (Alu, BC200, snaR). Notably, upregulation of Pol III transcription is frequently observed in cancer, and multiple ncRNA species are linked to both cancer progression and poor survival outcomes among cancer patients. In this review, we outline the basic features and functions of the Pol III transcriptome, and the evidence for dysregulation and dysfunction for each ncRNA in cancer. When taken together, recurrent patterns emerge, ranging from shared functional motifs that include molecular scaffolding and protein sequestration, overlapping protein interactions, and immunostimulatory activities, to the biogenesis of analogous small RNA fragments and noncanonical miRNAs, augmenting the function of the Pol III transcriptome and further broadening its role in cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Processing of Small RNAs RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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Affiliation(s)
- Sihang Zhou
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
| | - Kevin Van Bortle
- Department of Cell and Developmental Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
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Han XY, Li X, Zhao RY, Ma HZ, Yu M, Niu XD, Jin HJ, Wang YF, Liu DM, Cai H. Comprehensive analysis of prognostic value and immunotherapy prospect of brain cytoplasmic RNA1 in hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:644-664. [PMID: 37123057 PMCID: PMC10134208 DOI: 10.4251/wjgo.v15.i4.644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/18/2023] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
BACKGROUND The expression of brain cytoplasmic RNA1 (BCYRN1) is linked to the clinicopathology and prognosis of several types of cancers, among which hepatocellular carcinoma (HCC) is one of the most frequent types of cancer worldwide.
AIM To explore the prognostic value and immunotherapeutic potential of BCYRN1 in HCC by bioinformatics and meta-analysis.
METHODS Information was obtained from the Cancer Genome Atlas database. First, the correlation between BCYRN1 expression and prognosis and clinicopathologic characteristics of HCC patients was explored. Univariate and multivariate regression analyses were employed to examine the relationship between BCYRN1 and HCC prognosis. Secondly, potential functions and pathways were explored by means of enrichment analysis of differentially-expressed genes. The relationships between BCYRN1 expression and tumor microenvironment, immune cell infiltration, immune checkpoint, drug sensitivity and immunotherapy effect were also investigated. Finally, three major databases were searched and used to conduct a meta-analysis on the relationship between BCYRN1 expression and patient prognosis.
RESULTS BCYRN1 expression was significantly higher in HCC compared to normal tissues and was linked to a poor prognosis and clinicopathological characteristics. Enrichment analysis showed that BCYRN1 regulates the extracellular matrix and transmission of signaling molecules, participates in the metabolism of nutrients, such as proteins, and participates in tumor-related pathways. BCYRN1 expression was linked to the tumor microenvironment, immune cell infiltration, drug sensitivity and the efficacy of immunotherapy. Furthermore, the meta-analysis in this study showed that BCYRN1 overexpression was related to a worse outcome in HCC patients.
CONCLUSION Overexpression of BCYRN1 relates to poor prognosis and may be a potential prognostic factor and immunotherapeutic target in HCC.
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Affiliation(s)
- Xiao-Yong Han
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiong Li
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Graduate School, Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China
| | - Rang-Yin Zhao
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hai-Zhong Ma
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Miao Yu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Xiang-Dong Niu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hao-Jie Jin
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yong-Feng Wang
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- The First Clinical College of Medicine, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - De-Ming Liu
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hui Cai
- Gansu General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
- Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou 730000, Gansu Province, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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Shi SJ, Han DH, Zhang JL, Li Y, Yang AG, Zhang R. VIM‑AS1 promotes proliferation and drives enzalutamide resistance in prostate cancer via IGF2BP2‑mediated HMGCS1 mRNA stabilization. Int J Oncol 2023; 62:34. [PMID: 36734275 PMCID: PMC9911078 DOI: 10.3892/ijo.2023.5482] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 12/14/2022] [Indexed: 01/31/2023] Open
Abstract
VIM‑AS1, a cancer‑specific long non‑coding RNA, has been recognized as a pivotal regulator in multiple types of cancer. However, the role of VIM‑AS1 in the proliferation and resistance to anti‑androgen therapy of LNCaP and C4‑2 prostate cancer cells remains to be determined. In the current study, gain‑and‑loss experiments were used to investigate the effects of VIM‑AS on the proliferation and anti‑androgen therapy of LNCaP and C4‑2 cells. RNA sequencing, RNA pulldown and RNA immunoprecipitation were used to elucidate the underlying mechanism of VIM‑AS1 driving prostate progression. It was demonstrated that VIM‑AS1 was upregulated in C4‑2 cells, an established castration‑resistant prostate cancer (CRPC) cell line, compared with in LNCaP cells, an established hormone‑sensitive prostate cancer cell line. The present study further demonstrated that VIM‑AS1 was positively associated with the clinical stage of prostate cancer. Functionally, overexpression of VIM‑AS1 decreased the sensitivity to enzalutamide treatment and enhanced the proliferation of LNCaP cells in vitro, whereas knockdown of VIM‑AS1 increased the sensitivity to enzalutamide treatment and reduced the proliferation of C4‑2 cells in vitro and in vivo. Mechanistically, 3‑hydroxy‑3‑methylglutaryl‑CoA synthase 1 (HMGCS1) was identified as one of the direct downstream targets of VIM‑AS1, and VIM‑AS1 promoted HMGCS1 expression by enhancing HMGCS1 mRNA stability through a VIM‑AS1/insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2)/HMGCS1 RNA‑protein complex. Rescue assays indicated that knockdown of HMGCS1 expression ameliorated the increase in proliferation and enzalutamide resistance of prostate cancer cells induced by VIM‑AS1 overexpression. Overall, the present study determined the roles and mechanism of the VIM‑AS1/IGF2BP2/HMGCS1 axis in regulating proliferation and enzalutamide sensitivity of prostate cancer cells and suggested that VIM‑AS1 may serve as a novel therapeutic target for the treatment of patients with CRPC.
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Affiliation(s)
- Sheng-Jia Shi
- State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China,Department of Andrology, Reproduction Center, Northwest Women's and Children's Hospital, Xian Jiaotong University Health Science Center, Xi'an, Shaanxi 710004, P.R. China,Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710069, P.R. China
| | - Dong-Hui Han
- Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710069, P.R. China
| | - Jing-Liang Zhang
- Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710069, P.R. China
| | - Yu Li
- Department of Urology, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi 710069, P.R. China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China,Correspondence to: Professor Rui Zhang or Professor An-Gang Yang, State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, 169 Changle West Road, Xi'an, Shaanxi 710032, P.R. China, E-mail: , E-mail:
| | - Rui Zhang
- State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China,Correspondence to: Professor Rui Zhang or Professor An-Gang Yang, State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Medical University, 169 Changle West Road, Xi'an, Shaanxi 710032, P.R. China, E-mail: , E-mail:
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Dai L, Zhu R, Liu J, Li F, Wang J, Shang J. MSF-UBRW: An Improved Unbalanced Bi-Random Walk Method to Infer Human lncRNA-Disease Associations. Genes (Basel) 2022; 13:2032. [PMID: 36360269 PMCID: PMC9690797 DOI: 10.3390/genes13112032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/24/2022] [Accepted: 10/28/2022] [Indexed: 09/08/2024] Open
Abstract
Long-non-coding RNA (lncRNA) is a transcription product that exerts its biological functions through a variety of mechanisms. The occurrence and development of a series of human diseases are closely related to abnormal expression levels of lncRNAs. Scientists have developed many computational models to identify the lncRNA-disease associations (LDAs). However, many potential LDAs are still unknown. In this paper, a novel method, namely MSF-UBRW (multiple similarities fusion based on unbalanced bi-random walk), is designed to explore new LDAs. First, two similarities (functional similarity and Gaussian Interaction Profile kernel similarity) of lncRNAs are calculated and fused linearly, also for disease data. Then, the known association matrix is preprocessed. Next, the linear neighbor similarities of lncRNAs and diseases are calculated, respectively. After that, the potential associations are predicted based on unbalanced bi-random walk. The fusion of multiple similarities improves the prediction performance of MSF-UBRW to a large extent. Finally, the prediction ability of the MSF-UBRW algorithm is measured by two statistical methods, leave-one-out cross-validation (LOOCV) and 5-fold cross-validation (5-fold CV). The AUCs of 0.9391 in LOOCV and 0.9183 (±0.0054) in 5-fold CV confirmed the reliable prediction ability of the MSF-UBRW method. Case studies of three common diseases also show that the MSF-UBRW method can infer new LDAs effectively.
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Affiliation(s)
| | | | | | | | | | - Junliang Shang
- School of Computer Science, Qufu Normal University, Rizhao 276826, China
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12
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ZFP36 Inhibits Tumor Progression of Human Prostate Cancer by Targeting CDK6 and Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3611540. [PMID: 36111167 PMCID: PMC9470309 DOI: 10.1155/2022/3611540] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/26/2022] [Accepted: 08/04/2022] [Indexed: 11/21/2022]
Abstract
Background The expression of ZFP36 in previous study was reduced in prostate cancer (PCa) tissues as compared to benign prostate tissues, indicating the potential of ZFP36 as an auxiliary marker for PCa. Further evaluation was conducted in clinical samples for in vitro and in vivo experiments, to prove the potential possibility that ZFP36 dysregulation participated in the malignant phenotype of PCa, to determine its potential mechanism for tumor regulation, and to provide a new theoretical basis for gene therapy of PCa. Methods First, the expression of ZFP36 in prostate tissue and PCa tissue was explored, and the relationship between ZFP36 and clinical features of PCa patients was illustrated. Subsequently, the impact of ZFP36 on the biology of PCa cells and relevant downstream pathways of ZFP36's biological impact on PCa were elucidated. Finally, whether oxidative stress mediated the regulation of ZFP36 in PCa was verified by the determination of oxidative stress-related indicators and bioinformatics analysis. Results The downregulation of ZFP36 in PCa tissue had a positive correlation with high Gleason scores, advanced pathological stage, and biochemical recurrence. ZFP36 was identified as an independent prognostic factor for PCa patients' BCR-free survival (P = 0.022) by survival analysis. Following a subsequent experiment of function gain and loss, ZFP36 inhibited the proliferation, invasion, and migration in DU145 and 22RV1 cells and inhibits tumor growth in the mouse model. Additionally, high-throughput sequencing screened out CDK6 as the downstream target gene of ZFP36. Western blot/Q-PCR demonstrated that overexpression of ZFP36 could reduce the expression of CDK6 at both cellular and animal levels, and the dual-luciferase experiment and RIP experiment proved that CDK6 was the downstream target of ZFP36, indicating that CDK6 was a downstream target of ZFP36, which mediated tumor cell growth by blocking cell cycle at the G1 stage. Furthermore, ZFP36 inhibited oxidative stress in PCa cells. Conclusions In PCa, ZFP36 might be a tumor suppressor that regulated growth, invasion, and migration of PCa cells. The lately discovered ZFP36-CDK6 axis demonstrated the molecular mechanism of PCa progression to a certain extent which might act as a new possible therapeutic target of PCa therapy.
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13
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Levenson AS. Dietary stilbenes as modulators of specific miRNAs in prostate cancer. Front Pharmacol 2022; 13:970280. [PMID: 36091792 PMCID: PMC9449421 DOI: 10.3389/fphar.2022.970280] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Accumulated experimental data have suggested that natural plant products may be effective miRNA-modulating chemopreventive and therapeutic agents. Dietary polyphenols such as flavonoids, stilbenes, and lignans, among others, have been intensively studied for their miRNA-mediated cardioprotective, antioxidant, anti-inflammatory and anticancer properties. The aim of this review is to outline known stilbene-regulated miRNAs in cancer, with a special focus on the interplay between various miRNAs and MTA1 signaling in prostate cancer. MTA1 is an epigenetic reader and an oncogenic transcription factor that is overexpressed in advanced prostate cancer and metastasis. Not surprisingly, miRNAs that are linked to MTA1 affect cancer progression and the metastatic potential of cells. Studies led to the identification of MTA1-associated pro-oncogenic miRNAs, which are regulated by stilbenes such as resveratrol and pterostilbene. Specifically, it has been shown that inhibition of the activity of the MTA1 regulated oncogenic miR-17 family of miRNAs, miR-22, and miR-34a by stilbenes leads to inhibition of prostatic hyperplasia and tumor progression in mice and reduction of proliferation, survival and invasion of prostate cancer cells in vitro. Taken together, these findings implicate the use of resveratrol and its analogs as an attractive miRNA-mediated chemopreventive and therapeutic strategy in prostate cancer and the use of circulating miRNAs as potential predictive biomarkers for clinical development.
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Clinicopathological Significance and Prognostic Values of Long Noncoding RNA BCYRN1 in Cancer Patients: A Meta-Analysis and Bioinformatics Analysis. JOURNAL OF ONCOLOGY 2022; 2022:8903265. [PMID: 35874631 PMCID: PMC9303157 DOI: 10.1155/2022/8903265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/14/2022] [Indexed: 12/24/2022]
Abstract
Background Although combination therapies have substantially improved the clinical outcomes of cancer patients, the prognosis and early diagnosis remain unsatisfactory. As a result, it is critical to look for novel indicators linked to cancer. Despite a number of recent studies indicating that the lncRNA brain cytoplasmic RNA1(BCYRN1) may be a potential predictive biomarker in cancer patients, BCYRN1's prognostic value is still being debated. Methods We utilized PubMed, Embase, Web of Science, and the Cochrane Library to search for studies related to BCYRN1 until October 2021. Valid data were extracted after determining the articles according to the inclusion and exclusion criteria, and forest plots were made using Stata software. We used hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals to evaluate the relationship between abnormal BCYRN1 expression and patient prognosis and clinicopathological characteristics. Results Meta-analysis revealed that increased BCYRN1 expression was associated with both overall tumor survival (OS; HR = 1.84, 95% CI 1.51–2.25, p < 0.0001) and disease-free survival (DFS; HR = 1.65, 95% CI 1.20–2.26, p=0.002). Furthermore, a strong association was discovered between increased BCYRN1 expression and tumor invasion depth (OR = 2.11, 95% CI 1.49–2.99, p=0.000), clinical stage (OR = 2.52, 95% CI 1.18–5.37, p=0.017), and distant tumor metastasis (OR = 4.19, 95% CI 1.45–12.05, p=0.008). Conclusions We found that high BCYRN1 expression was associated with poor survival prognosis and aggressive clinicopathological characteristics in various cancers, indicating that it is a potential prognostic indicator as well as a therapeutic target. Further research is needed on pan-cancer cohorts to determine the clinical relevance of BCYRN1 in distinct cancer types.
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15
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Major Role for Cellular MicroRNAs, Long Noncoding RNAs (lncRNAs), and the Epstein-Barr Virus-Encoded BART lncRNA during Tumor Growth
In Vivo. mBio 2022; 13:e0065522. [PMID: 35435703 PMCID: PMC9239068 DOI: 10.1128/mbio.00655-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
This study assessed the effects of Epstein-Barr virus (EBV) and one form of virally encoded BART long noncoding RNAs (lncRNAs) on cellular expression in epithelial cells grown in vitro and as tumors in vivo determined by high-throughput RNA sequencing of mRNA and small RNAs. Hierarchical clustering based on gene expression distinguished the cell lines from the tumors and distinguished the EBV-positive tumors and the BART tumors from the EBV-negative tumors. EBV and BART expression also induced specific expression changes in cellular microRNAs (miRs) and lncRNAs. Multiple known and predicted targets of the viral miRs, the induced cellular miRs, and lncRNAs were identified in the altered gene set. The changes in expression in vivo indicated that the suppression of growth pathways in vivo reflects increased expression of cellular miRs in all tumors. In the EBV and BART tumors, many of the targets of the induced miRs were not changed and the seed sequences of the nonfunctional miRs were found to have homologous regions within the BART lncRNA. The inhibition of these miR effects on known targets suggests that these induced miRs have reduced function due to sponging by the BART lncRNA. This composite analysis identified the effects of EBV on cellular miRs and lncRNAs with a functional readout through identification of the simultaneous effects on gene expression. Major shifts in gene expression in vivo are likely mediated by effects on cellular noncoding RNAs. Additionally, a predicted property of the BART lncRNA is to functionally inhibit the induced cellular miRs.
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16
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da Silveira WA, Renaud L, Hazard ES, Hardiman G. miRNA and lncRNA Expression Networks Modulate Cell Cycle and DNA Repair Inhibition in Senescent Prostate Cells. Genes (Basel) 2022; 13:genes13020208. [PMID: 35205253 PMCID: PMC8872619 DOI: 10.3390/genes13020208] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 01/16/2022] [Accepted: 01/20/2022] [Indexed: 01/27/2023] Open
Abstract
Cellular senescence is a state of permanent growth arrest that arises once cells reach the limit of their proliferative capacity. It creates an inflammatory microenvironment favouring the initiation and progression of various age-related diseases, including prostate cancer. Non-coding RNAs (ncRNAs) have emerged as important regulators of cellular gene expression. Nonetheless, very little is known about the interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and how deregulation of ncRNA networks promotes cellular senescence. To investigate this, human prostate epithelial cells were cultured through different passages until senescent, and their RNA was extracted and sequenced using RNA sequencing (RNAseq) and microRNA sequencing (miRNA-seq) miRNAseq. Differential expression (DE) gene analysis was performed to compare senescent and proliferating cells with Limma, miRNA-target interactions with multiMiR, lncRNA-target interactions using TCGA data and network evaluation with miRmapper. We found that miR-335-3p, miR-543 and the lncRNAs H19 and SMIM10L2A all play central roles in the regulation of cell cycle and DNA repair processes. Expression of most genes belonging to these pathways were down-regulated by senescence. Using the concept of network centrality, we determined the top 10 miRNAs and lncRNAs, with miR-335-3p and H19 identified as the biggest hubs for miRNAs and lncRNA respectively. These ncRNAs regulate key genes belonging to pathways involved in cell senescence and prostate cancer demonstrating their central role in these processes and opening the possibility for their use as biomarkers or therapeutic targets to mitigate against prostate ageing and carcinogenesis.
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Affiliation(s)
- Willian A. da Silveira
- Department of Biological Sciences, Science Centre, School of Health, Science and Wellbeing, Staffordshire University, Leek Road, Stoke-on-Trent ST4 2DF, UK;
- Faculty of Medicine, Health and Life Sciences, Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast, 19 Chlorine Gardens, Belfast BT9 5DL, UK
| | - Ludivine Renaud
- Department of Medicine, Medical University of South Carolina, MSC 403, 171 Ashley Ave Suite 419, Charleston, SC 29425, USA; (L.R.); (E.S.H.)
| | - Edward S. Hazard
- Department of Medicine, Medical University of South Carolina, MSC 403, 171 Ashley Ave Suite 419, Charleston, SC 29425, USA; (L.R.); (E.S.H.)
| | - Gary Hardiman
- Faculty of Medicine, Health and Life Sciences, Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast, 19 Chlorine Gardens, Belfast BT9 5DL, UK
- Department of Medicine, Medical University of South Carolina, MSC 403, 171 Ashley Ave Suite 419, Charleston, SC 29425, USA; (L.R.); (E.S.H.)
- Correspondence: ; Tel.: +44-(0)-28-9097-6514
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17
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Zhao C, Jiang Q, Chen L, Chen W. LncRNA LINC01535 promotes colorectal cancer development and chemoresistance by sponging miR-761. Exp Ther Med 2021; 22:685. [PMID: 33986850 PMCID: PMC8112154 DOI: 10.3892/etm.2021.10117] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human cancer types and a leading cause of cancer-related death. Accumulating evidence has confirmed that long non-coding RNAs have crucial roles in CRC progression. In the present study, the biological roles of LINC01535 were investigated and the interaction between long intergenic non-coding RNA (LINC)01535 and microRNA (miR)-761 in CRC was explored. LINC01535 expression was observed to be upregulated in CRC tissues and cell lines. A functional study suggested that LINC01535 silencing inhibited CRC cell proliferation and invasion but enhanced cisplatin sensitivity of CRC cells, while co-transfection with a miR-761 inhibitor reversed these biological effects. A luciferase reporter assay demonstrated that LINC01535 regulated miR-761 directly and RNA-binding protein immunoprecipitation further confirmed that the suppression of LINC01535 by miR-761 was via an RNA-induced silencing complex. Finally, knockdown of LINC01535 inhibited the growth of CRC cells in vivo. Collectively, the results suggested that LINC01535 exerts oncogenic functions in CRC by sponging miR-761. In conclusion, the present study indicated that LINC01535 promoted CRC progression through sponging miR-761, and may serve as a potential diagnostic biomarker and therapeutic target for CRC.
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Affiliation(s)
- Changjie Zhao
- Endoscopy Center, Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
| | - Qi Jiang
- Department of Gastroenterology, Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
| | - Lin Chen
- Department of Gastroenterology, Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
| | - Wei Chen
- Department of Gastroenterology, Affiliated Dongtai Hospital of Nantong University, Dongtai, Jiangsu 224200, P.R. China
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18
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Núñez-Álvarez Y, Suelves M. HDAC11: a multifaceted histone deacetylase with proficient fatty deacylase activity and its roles in physiological processes. FEBS J 2021; 289:2771-2792. [PMID: 33891374 DOI: 10.1111/febs.15895] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/22/2021] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
The histone deacetylases (HDACs) family of enzymes possess deacylase activity for histone and nonhistone proteins; HDAC11 is the latest discovered HDAC and the only member of class IV. Besides its shared HDAC family catalytical activity, recent studies underline HDAC11 as a multifaceted enzyme with a very efficient long-chain fatty acid deacylase activity, which has open a whole new field of action for this protein. Here, we summarize the importance of HDAC11 in a vast array of cellular pathways, which has been recently highlighted by discoveries about its subcellular localization, biochemical features, and its regulation by microRNAs and long noncoding RNAs, as well as its new targets and interactors. Additionally, we discuss the recent work showing the consequences of HDAC11 dysregulation in brain, skeletal muscle, and adipose tissue, and during regeneration in response to kidney, skeletal muscle, and vascular injuries, underscoring HDAC11 as an emerging hub protein with physiological functions that are much more extensive than previously thought, and with important implications in human diseases.
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Affiliation(s)
| | - Mònica Suelves
- Germans Trias i Pujol Research Institute, Badalona, Spain
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19
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Ding X, Xu X, He XF, Yuan Y, Chen C, Shen XY, Su S, Chen Z, Xu ST, Huang YH. Muscleblind-like 1 antisense RNA 1 inhibits cell proliferation, invasion, and migration of prostate cancer by sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR signaling. Bioengineered 2021; 12:803-814. [PMID: 33648424 PMCID: PMC8806234 DOI: 10.1080/21655979.2021.1890383] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The present study aimed to investigate the role and underlying mechanisms of long non-coding RNA (lncRNA) muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) in the progression of Prostate cancer (PCa). MBNL1-AS1 and microRNA (miR)-181a-5p expression in PCa tissues and several human PCa cell lines were analyzed, respectively, using StarBasev3.0 project and RT-qPCR assay. After MBNL1-AS1 overexpression, cell proliferation, invasion and migration were, respectively, evaluated using CCK-8, colony formation, transwell and wound healing assays. Dual luciferase assay were used for analysis of the interactions among MBNL1-AS1, miR-181a-5p, and phosphatase and tensin homolog (PTEN). Subsequently, the expression of PTEN and proteins in PI3K/AKT/mTOR signaling was examined using western blot analysis after transfection with miR-181a-5p mimic. The rescue assays were performed to investigate the effects of MBNL1-AS1 and miR-181a-5p on the functions of PCa cells and the expression of PTEN/PI3K/AKT/mTOR signaling by co-transfection with MBNL1-AS1 plasmid and miR-181a-5p mimic. Results indicated that MBNL1-AS1 was conspicuously downregulated while miR-181a-5p upregulating in PCa tissues and cell lines. MBNL1-AS1 overexpression decreased the abilities of cell proliferation, invasion, and migration. Further study revealed that MBNL1-AS1 acted as a sponge for miR-181a-5p and positively regulated PTEN by a sponge effect. Additionally, rescue assays proved that the effect of MBNL1-AS1-upregulation on the proliferation, invasion, and migration of PCa cells was dependent on miR-181a-5p. Furthermore, miR-181a-5p overexpression counteracted the expression of PTEN and proteins in PI3K/AKT/mTOR signaling exerted by MBNL1-AS1-upregulation in PCa cells. This study suggests that MBNL1-AS1 inhibits the progression of PCa via sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Xiang Ding
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xu Xu
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xue-Feng He
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ye Yuan
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chuang Chen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xin-Yu Shen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Sai Su
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhang Chen
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Song-Tao Xu
- Department of Clinical Medicine, Luohe Medical College, Luohe, China
| | - Yu-Hua Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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20
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Ghafouri-Fard S, Dashti S, Hussen BM, Farsi M, Taheri M. BCYRN1: An oncogenic lncRNA in diverse cancers. Pathol Res Pract 2021; 220:153385. [PMID: 33647864 DOI: 10.1016/j.prp.2021.153385] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 12/14/2022]
Abstract
Brain cytoplasmic 200 (BC200) or alternatively named as brain cytoplasmic RNA 1 (BCYRN1) is a long non-coding RNA (lncRNA) primarily identified in the neurons. In addition to its participation in the pathogenesis of neurodegenerative disorders, it partake in the carcinogenesis process. Numerous in vitro studies have reported elevation of expression of BCYRN1 in cancer cell lines. Short hairpin-RNA-mediated silencing of BCYRN1 has attenuated growth of tumors in the animal models. Independent studies in esophageal squamous cell cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and non-small cell lung cancer have demonstrated association between elevated BCYRN1 levels and poor survival of patients. Taken together, BCYRN1 is an appropriate candidate for targeted therapies in the field of cancer.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sepideh Dashti
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Molood Farsi
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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