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      Twist1: A Double-Edged Sword in Kidney Diseases

      , *

      Kidney Diseases

      S. Karger AG

      Twist1, Chronic kidney disease, Signaling transduction

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          Background: Twist1 is a basic helix-loop-helix domain containing transcription factor that regulates cell differentiation, migration, proliferation, survival, and inflammatory responses by transcriptionally regulating a wide range of downstream target genes. Its homologous protein, Twist2, shares many structural and functional similarities with Twist1. Summary: Accumulating evidence from both preclinical and clinical studies suggests that Twist1 is a pivotal regulator of several forms of renal disease. Twist1 is persistently activated following renal insults, particularly in chronic kidney diseases, and contributes to the renal inflammatory responses, tubular cell transformation programs, and possibly fibroblast activation, all of which are involved in the initiation and progression of kidney diseases. Key Message: This review will specifically focus on Twist1 and outline our understanding of its functions in kidney disorders along with the introduction of Twist2 where pertinent. The thorough knowledge of Twist1’s actions in the pathogenesis of kidney diseases should facilitate the development of novel therapeutics for kidney injury.

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          Most cited references 68

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          Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence.

          Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.
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            Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.

            The epithelial-mesenchymal transition (EMT), one of the main mechanisms underlying development of cancer metastasis, induces stem-like properties in epithelial cells. Bmi1 is a polycomb-group protein that maintains self-renewal, and is frequently overexpressed in human cancers. Here, we show the direct regulation of BMI1 by the EMT regulator, Twist1. Furthermore, Twist1 and Bmi1 were mutually essential to promote EMT and tumour-initiating capability. Twist1 and Bmi1 act cooperatively to repress expression of both E-cadherin and p16INK4a. In patients with head and neck cancers, increased levels of both Twist1 and Bmi1 correlated with downregulation of E-cadherin and p16INK4a, and was associated with the worst prognosis. These results suggest that Twist1-induced EMT and tumour-initiating capability in cancer cells occurs through chromatin remodelling, which leads to unfavourable clinical outcomes.
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              Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms.

              This article reviews the molecular structure, expression pattern, physiological function, pathological roles and molecular mechanisms of Twist1 in development, genetic disease and cancer. Twist1 is a basic helix-loop-helix domain-containing transcription factor. It forms homo- or hetero-dimers in order to bind the Nde1 E-box element and activate or repress its target genes. During development, Twist1 is essential for mesoderm specification and differentiation. Heterozygous loss-of-function mutations of the human Twist1 gene cause several diseases including the Saethre-Chotzen syndrome. The Twist1-null mouse embryos die with unclosed cranial neural tubes and defective head mesenchyme, somites and limb buds. Twist1 is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twist1 is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-1α, integrin-linked kinase and NF-κB. Twist1 significantly enhances epithelial-mesenchymal transition (EMT) and cancer cell migration and invasion, hence promoting cancer metastasis. Twist1 promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmi1, AKT2, YB-1, etc. Emerging evidence also suggests that Twist1 plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Further understanding of the mechanisms by which Twist1 promotes metastasis and identification of Twist1 functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.

                Author and article information

                Kidney Diseases
                S. Karger AG
                July 2020
                17 January 2020
                : 6
                : 4
                : 247-257
                Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Durham, North Carolina, USA
                Author notes
                *Steven D. Crowley, Division of Nephrology, Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers, Box 103015 DUMC, Durham, NC 27710 (USA), E-Mail
                505188 Kidney Dis 2020;6:247–257
                © 2020 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Pages: 11
                Review Article

                Cardiovascular Medicine, Nephrology

                Signaling transduction, Twist1, Chronic kidney disease


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