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Transcription Factors as Therapeutic Targets

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 101660

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Special Issue Editor

Dr. Takaomi Sanda

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Guest Editor

1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
2. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Interests: transcription; transcription factor; enhancer; core regulatory circuit; stem cells; hematopoiesis; acute leukemia; T-cell acute lymphoblastic leukemia; oncogene; TAL1
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Deregulation of transcription factor genes are frequently observed in various human diseases, such as cancer. Understanding the molecular pathogenesis, as well as the development of therapeutic approaches, are crucial to further advance the treatment outcome. Although the feasibility of transcription factors as therapeutic targets has long been realized, the development of drugs is still very challenging due to several pharmacological and biological reasons. Therefore, an improved knowledge is necessary to make transcription factors “actionable”. This Special Issue aims to provide a forum for the dissemination of the latest information on new approaches and methods targeting transcription factors, and with methods of testing their success in cancer or other human diseases.

Dr. Takaomi Sanda
Guest Editor

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Keywords

Transcription
Transcription factor
Enhancer
Epigenetics
Small-molecules
Cancer
Immunological diseases
Infectious diseases

Published Papers (13 papers)

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Research

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8 pages, 1602 KiB

Open AccessFeature PaperArticle

Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBPα

by Radhakrishnan Sridhar, Hisashi Takei, Riyaz Syed, Ikei S. Kobayashi, Liu Bee Hui, Ahmed Kamal, Daniel G. Tenen and Susumu S. Kobayashi

Molecules 2018, 23(8), 1938; https://doi.org/10.3390/molecules23081938 - 03 Aug 2018

Cited by 5 | Viewed by 4134

Abstract

The CCAAT enhancer-binding protein α (C/EBPα) plays an important role in myeloid cell differentiation and in the enhancement of C/EBPα expression/activity, which can lead to granulocytic differentiation in acute myeloid leukemia (AML) cells. We found that styryl quinazolinones induce upregulation of C/EBPα expression, and thereby induce myeloid differentiation in human myeloid leukemia cell lines. We screened a series of active styryl quinazolinones and evaluated the structure–activity relationship (SAR) of these small molecules in inducing C/EBPα expression—thereby prompting the leukemic cells to differentiate. We observed that compound 78 causes differentiation at 3 μM concentration, while 1 induces differentiation at 10 μM concentration. We also observed an increase in the expression of neutrophil differentiation marker CD11b upon treatment with 78. Both the C/EBPα and C/EBPε levels were found to be upregulated by treatment with 78. These SAR findings are inspiration to develop further modified styryl quinazolinones, in the path of this novel differentiation therapy, which can contribute to the care of patients with AML. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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13 pages, 2036 KiB

Open AccessArticle

Anti-Tumorigenic Activity of Chrysin from Oroxylum indicum via Non-Genotoxic p53 Activation through the ATM-Chk2 Pathway

by Mai Nagasaka, Ryoko Hashimoto, Yasumichi Inoue, Kan’ichiro Ishiuchi, Michiyo Matsuno, Yuka Itoh, Muneshige Tokugawa, Nobumichi Ohoka, Daisuke Morishita, Hajime Mizukami, Toshiaki Makino and Hidetoshi Hayashi

Molecules 2018, 23(6), 1394; https://doi.org/10.3390/molecules23061394 - 08 Jun 2018

Cited by 32 | Viewed by 4899

Abstract

The p53 tumor suppressor plays critical roles in cell cycle regulation and apoptotic cell death in response to various cellular stresses, thereby preventing cancer development. Therefore, the activation of p53 through small molecules is an attractive therapeutic strategy for the treatment of cancers retaining wild-type p53. We used a library of 700 Myanmar wild plant extracts to identify small molecules that induce p53 transcriptional activity. A cell-based screening method with a p53-responsive luciferase-reporter assay system revealed that an ethanol extract of Oroxylum indicum bark increased p53 transcriptional activity. Chrysin was isolated and identified as the active ingredient in the O. indicum bark extract. A treatment with chrysin increased p53 protein expression and the p53-mediated expression of downstream target genes, and decreased cell viability in MCF7 cells, but not in p53-knockdown MCF7 cells. We also found that chrysin activated the ATM-Chk2 pathway in the absence of DNA damage. Hence, the inactivation of the ATM-Chk2 pathway suppressed p53 activation induced by chrysin. These results suggest the potential of chrysin as an anti-cancer drug through the activation of p53 without DNA damage. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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11 pages, 1718 KiB

Open AccessArticle

Detecting Differential Transcription Factor Activity from ATAC-Seq Data

by Ignacio J. Tripodi, Mary A. Allen and Robin D. Dowell

Molecules 2018, 23(5), 1136; https://doi.org/10.3390/molecules23051136 - 10 May 2018

Cited by 28 | Viewed by 12957

Abstract

Transcription factors are managers of the cellular factory, and key components to many diseases. Many non-coding single nucleotide polymorphisms affect transcription factors, either by directly altering the protein or its functional activity at individual binding sites. Here we first briefly summarize high-throughput approaches to studying transcription factor activity. We then demonstrate, using published chromatin accessibility data (specifically ATAC-seq), that the genome-wide profile of TF recognition motifs relative to regions of open chromatin can determine the key transcription factor altered by a perturbation. Our method of determining which TFs are altered by a perturbation is simple, is quick to implement, and can be used when biological samples are limited. In the future, we envision that this method could be applied to determine which TFs show altered activity in response to a wide variety of drugs and diseases. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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9 pages, 2217 KiB

Open AccessCommunication

Design, Synthesis, and In Vitro Evaluation of Novel Histone H3 Peptide-Based LSD1 Inactivators Incorporating α,α-Disubstituted Amino Acids with γ-Turn-Inducing Structures

by Yosuke Ota, Taeko Kakizawa, Yukihiro Itoh and Takayoshi Suzuki

Molecules 2018, 23(5), 1099; https://doi.org/10.3390/molecules23051099 - 06 May 2018

Cited by 9 | Viewed by 4639

Abstract

Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1. Based on this, we designed and synthesized novel histone H3 peptide-based LSD1 inactivators 2a–c by incorporating various α,α-disubstituted amino acids with γ-turn-inducing structures. Among synthetic peptides 2a–c, peptide 2b incorporating two 1-aminocyclohexanecarboxylic acids at both sides of a lysine residue bearing a trans-2-phenylcyclopropylamine (PCPA) moiety, which is a pharmacophore for LSD1 inactivation, was the most potent and selective LSD1 inactivator. These findings are useful for the further development of histone H3 peptide-based LSD1 inactivators. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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4335 KiB

Open AccessArticle

Thymoquinone Inhibits the Migration and Invasive Characteristics of Cervical Cancer Cells SiHa and CaSki In Vitro by Targeting Epithelial to Mesenchymal Transition Associated Transcription Factors Twist1 and Zeb1

by Jun Li, Md. Asaduzzaman Khan, Chunli Wei, Jingliang Cheng, Hanchun Chen, Lisha Yang, Iqra Ijaz and Junjiang Fu

Molecules 2017, 22(12), 2105; https://doi.org/10.3390/molecules22122105 - 04 Dec 2017

Cited by 57 | Viewed by 5960

Abstract

Cervical cancer is one of the most common gynecological malignant tumors worldwide, for which chemotherapeutic strategies are limited due to their non-specific cytotoxicity and drug resistance. The natural product thymoquinone (TQ) has been reported to target a vast number of signaling pathways in carcinogenesis in different cancers, and hence is regarded as a promising anticancer molecule. Inhibition of epithelial to mesenchymal transition (EMT) regulators is an important approach in anticancer research. In this study, TQ was used to treat the cervical cancer cell lines SiHa and CaSki to investigate its effects on EMT-regulatory proteins and cancer metastasis. Our results showed that TQ has time-dependent and dose-dependent cytotoxic effects, and it also inhibits the migration and invasion processes in different cervical cancer cells. At the molecular level, TQ treatment inhibited the expression of Twist1, Zeb1 expression, and increased E-Cadherin expression. Luciferase reporter assay showed that TQ decreases the Twist1 and Zeb1 promoter activities respectively, indicating that Twist1 and Zeb1 might be the direct target of TQ. TQ also increased cellular apoptosis in some extent, but apoptotic genes/proteins we tested were not significant affected. We conclude that TQ inhibits the migration and invasion of cervical cancer cells, probably via Twist1/E-Cadherin/EMT or/and Zeb1/E-Cadherin/EMT, among other signaling pathways. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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Review

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22 pages, 1439 KiB

Open AccessReview

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

by Thanh Hung Nguyen and Frederic G. Barr

Molecules 2018, 23(11), 2798; https://doi.org/10.3390/molecules23112798 - 28 Oct 2018

Cited by 44 | Viewed by 9931

Abstract

Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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25 pages, 37157 KiB

Open AccessReview

ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer

by Ian Y. Luk, Camilla M. Reehorst and John M. Mariadason

Molecules 2018, 23(9), 2191; https://doi.org/10.3390/molecules23092191 - 30 Aug 2018

Cited by 70 | Viewed by 7479

Abstract

The epithelium-specific ETS (ESE) transcription factors (ELF3, ELF5, EHF and SPDEF) are defined by their highly conserved ETS DNA binding domain and predominant epithelial-specific expression profile. ESE transcription factors maintain normal cell homeostasis and differentiation of a number of epithelial tissues, and their genetic alteration and deregulated expression has been linked to the progression of several epithelial cancers. Herein we review the normal function of the ESE transcription factors, the mechanisms by which they are dysregulated in cancers, and the current evidence for their role in cancer progression. Finally, we discuss potential therapeutic strategies for targeting or reactivating these factors as a novel means of cancer treatment. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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51 pages, 2982 KiB

Open AccessReview

Targeting Transcription Factors for Cancer Treatment

by Mélanie Lambert, Samy Jambon, Sabine Depauw and Marie-Hélène David-Cordonnier

Molecules 2018, 23(6), 1479; https://doi.org/10.3390/molecules23061479 - 19 Jun 2018

Cited by 228 | Viewed by 19053

Abstract

Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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13 pages, 1360 KiB

Open AccessReview

Transcription Factors as Therapeutic Targets in Chronic Kidney Disease

by Akihito Hishikawa, Kaori Hayashi and Hiroshi Itoh

Molecules 2018, 23(5), 1123; https://doi.org/10.3390/molecules23051123 - 09 May 2018

Cited by 20 | Viewed by 5383

Abstract

The growing number of patients with chronic kidney disease (CKD) is recognized as an emerging problem worldwide. Recent studies have indicated that deregulation of transcription factors is associated with the onset or progression of kidney disease. Several clinical trials indicated that regression of CKD may be feasible via activation of the transcription factor nuclear factor erythroid-2 related factor 2 (Nrf2), which suggests that transcription factors may be potential drug targets for CKD. Agents stabilizing hypoxia-inducible factor (HIF), which may be beneficial for renal anemia and renal protection, are also now under clinical trial. Recently, we have reported that the transcription factor Kruppel-like factor 4 (KLF4) regulates the glomerular podocyte epigenome, and that the antiproteinuric effect of the renin–angiotensin system blockade may be partially mediated by KLF4. KLF4 is one of the Yamanaka factors that induces iPS cells and is reported to be involved in epigenetic remodeling. In this article, we summarize the transcription factors associated with CKD and particularly focus on the possibility of transcription factors being novel drug targets for CKD through epigenetic modulation. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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15 pages, 1496 KiB

Open AccessFeature PaperReview

Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia

by Regina Wan Ju Wong, Takashi Ishida and Takaomi Sanda

Molecules 2018, 23(5), 1057; https://doi.org/10.3390/molecules23051057 - 02 May 2018

Cited by 8 | Viewed by 6236

Abstract

Cancer cells are highly reliant on certain molecular pathways, which support their survival and proliferation. The fundamental concept of molecularly targeted therapy is to target a protein that is specifically deregulated or overexpressed in cancer cells. However, drug resistance and tumor heterogeneity are major obstacles in the development of specific inhibitors. Additionally, many driver oncogenes exert their oncogenic property via abnormal expression without having genetic mutations. Interestingly, recent accumulating evidence has demonstrated that many critical cancer genes are driven by a unique class of enhancers termed super-enhancers. Genes associated with super-enhancers are relatively more susceptible to the inhibition of general transcriptional machinery compared with genes that are regulated by typical enhancers. Cancer cells are more sensitive to treatment with small-molecule inhibitors of CDK7 or BRD4 than non-transformed cells. These findings proposed a novel strategy to identify functionally important genes as well as novel therapeutic modalities in cancer. This approach would be particularly useful for genetically complicated cancers, such as adult T-cell leukemia (ATL), whereby a large mutational burden is present, but the functional consequences of each mutation have not been well-studied. In this review, we discuss recent findings on super-enhancers, underlying mechanisms, and the efficacy of small-molecule transcriptional inhibitors in ATL. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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19 pages, 883 KiB

Open AccessReview

Targeting GLI Transcription Factors in Cancer

by Miroslava Didiasova, Liliana Schaefer and Malgorzata Wygrecka

Molecules 2018, 23(5), 1003; https://doi.org/10.3390/molecules23051003 - 24 Apr 2018

Cited by 54 | Viewed by 7749

Abstract

Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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15 pages, 4362 KiB

Open AccessReview

HIV Tat/P-TEFb Interaction: A Potential Target for Novel Anti-HIV Therapies

by Kaori Asamitsu, Koh Fujinaga and Takashi Okamoto

Molecules 2018, 23(4), 933; https://doi.org/10.3390/molecules23040933 - 17 Apr 2018

Cited by 24 | Viewed by 5717

Abstract

Transcription is a crucial step in the life cycle of the human immunodeficiency virus type 1 (HIV 1) and is primarily involved in the maintenance of viral latency. Both viral and cellular transcription factors, including transcriptional activators, suppressor proteins and epigenetic factors, are involved in HIV transcription from the proviral DNA integrated within the host cell genome. Among them, the virus-encoded transcriptional activator Tat is the master regulator of HIV transcription. Interestingly, unlike other known transcriptional activators, Tat primarily activates transcriptional elongation and initiation by interacting with the cellular positive transcriptional elongation factor b (P-TEFb). In this review, we describe the molecular mechanism underlying how Tat activates viral transcription through interaction with P-TEFb. We propose a novel therapeutic strategy against HIV replication through blocking Tat action. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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17 pages, 1871 KiB

Open AccessFeature PaperReview

Taming the Notch Transcriptional Regulator for Cancer Therapy

by Luca Tamagnone, Serena Zacchigna and Michael Rehman

Molecules 2018, 23(2), 431; https://doi.org/10.3390/molecules23020431 - 15 Feb 2018

Cited by 37 | Viewed by 6632

Abstract

Notch signaling is a highly conserved pathway in all metazoans, which is deeply involved in the regulation of cell fate and differentiation, proliferation and migration during development. Research in the last decades has shown that the various components of the Notch signaling cascade are either upregulated or activated in human cancers. Therefore, its downregulation stands as a promising and powerful strategy for cancer therapy. Here, we discuss the recent advances in the development of small molecule inhibitors, blocking antibodies and oligonucleotides that hinder Notch activity, and their outcome in clinical trials. Although Notch was initially identified as an oncogene, later studies showed that it can also act as a tumor suppressor in certain contexts. Further complexity is added by the existence of numerous Notch family members, which exert different activities and can be differentially targeted by inhibitors, potentially accounting for contradictory data on their therapeutic efficacy. Notably, recent evidence supports the rationale for combinatorial treatments including Notch inhibitors, which appear to be more effective than single agents in fighting cancer. Full article

(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)

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