Regulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and Cancers

Powerful bioinformatics tools have provided a wealth of novel miRNA–transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.

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KCNQ1OT1: An Oncogenic Long Noncoding RNA

Biomolecules ◽

10.3390/biom11111602 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1602

Author(s):

Patrice Cagle ◽

Qi Qi ◽

Suryakant Niture ◽

Deepak Kumar

Keyword(s):

Noncoding Rna ◽

Molecular Mechanisms ◽

Vital Role ◽

Migration And Invasion ◽

Biological Functions ◽

Aberrant Expression ◽

Human Cancers ◽

Oral Melanoma ◽

Opposite Strand

Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes a lncRNA from the opposite strand of KCNQ1 in the CDKN1C/KCNQ1OT1 cluster that is reported to play a vital role in the development and progression of cancer. KCNQ1OT1 regulates cancer cell proliferation, cell cycle, migration and invasion, metastasis, glucose metabolism, and immune evasion. The aberrant expression of KCNQ1OT1 in cancer patients is associated with poor prognosis and decreased survival. This review summarizes recent literature related to the biological functions and molecular mechanisms of KCNQ1OT1 in various human cancers, including colorectal, bladder, breast, oral, melanoma, osteosarcoma, lung, glioma, ovarian, liver, acute myeloid leukemia, prostate, and gastric. We also discuss the role of KCNQ1OT1 as a promising diagnostic biomarker and a novel therapeutic target in human cancers.

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NOB1: A Potential Biomarker or Target in Cancer

Current Drug Targets ◽

10.2174/1389450120666190308145346 ◽

2019 ◽

Vol 20 (10) ◽

pp. 1081-1089

Author(s):

Weiwei Ke ◽

Zaiming Lu ◽

Xiangxuan Zhao

Keyword(s):

Cancer Treatment ◽

Molecular Mechanisms ◽

Rna Binding ◽

Binding Protein ◽

Tumor Development ◽

Anticancer Therapy ◽

Research Progress ◽

Normal Tissues ◽

Potential Biomarker

Human NIN1/RPN12 binding protein 1 homolog (NOB1), an RNA binding protein, is expressed ubiquitously in normal tissues such as the lung, liver, and spleen. Its core physiological function is to regulate protease activities and participate in maintaining RNA metabolism and stability. NOB1 is overexpressed in a variety of cancers, including pancreatic cancer, non-small cell lung cancer, ovarian cancer, prostate carcinoma, osteosarcoma, papillary thyroid carcinoma, colorectal cancer, and glioma. Although existing data indicate that NOB1 overexpression is associated with cancer growth, invasion, and poor prognosis, the molecular mechanisms behind these effects and its exact roles remain unclear. Several studies have confirmed that NOB1 is clinically relevant in different cancers, and further research at the molecular level will help evaluate the role of NOB1 in tumors. NOB1 has become an attractive target in anticancer therapy because it is overexpressed in many cancers and mediates different stages of tumor development. Elucidating the role of NOB1 in different signaling pathways as a potential cancer treatment will provide new ideas for existing cancer treatment methods. This review summarizes the research progress made into NOB1 in cancer in the past decade; this information provides valuable clues and theoretical guidance for future anticancer therapy by targeting NOB1.

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The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

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Endothelin 1-induced retinal ganglion cell death is largely mediated by JUN activation

Cell Death and Disease ◽

10.1038/s41419-020-02990-0 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Olivia J. Marola ◽

Stephanie B. Syc-Mazurek ◽

Gareth R. Howell ◽

Richard T. Libby

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Ganglion Cells ◽

Retinal Vessel ◽

Vessel Diameter ◽

Retinal Ganglion ◽

Retinal Ganglion Cell Death ◽

Ganglion Cell Death

Abstract Glaucoma is a neurodegenerative disease characterized by loss of retinal ganglion cells (RGCs), the output neurons of the retina. Multiple lines of evidence show the endothelin (EDN, also known as ET) system is important in glaucomatous neurodegeneration. To date, the molecular mechanisms within RGCs driving EDN-induced RGC death have not been clarified. The pro-apoptotic transcription factor JUN (the canonical target of JNK signaling) and the endoplasmic reticulum stress effector and transcription factor DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been shown to act downstream of EDN receptors. Previous studies demonstrated that JUN and DDIT3 were important regulators of RGC death after glaucoma-relevant injures. Here, we characterized EDN insult in vivo and investigated the role of JUN and DDIT3 in EDN-induced RGC death. To accomplish this, EDN1 ligand was intravitreally injected into the eyes of wildtype, Six3-cre+Junfl/fl (Jun−/−), Ddit3 null (Ddit3−/−), and Ddit3−/−Jun−/− mice. Intravitreal EDN1 was sufficient to drive RGC death in vivo. EDN1 insult caused JUN activation in RGCs, and deletion of Jun from the neural retina attenuated RGC death after EDN insult. However, deletion of Ddit3 did not confer significant protection to RGCs after EDN1 insult. These results indicate that EDN caused RGC death via a JUN-dependent mechanism. In addition, EDN signaling is known to elicit potent vasoconstriction. JUN signaling was shown to drive neuronal death after ischemic insult. Therefore, the effects of intravitreal EDN1 on retinal vessel diameter and hypoxia were explored. Intravitreal EDN1 caused transient retinal vasoconstriction and regions of RGC and Müller glia hypoxia. Thus, it remains a possibility that EDN elicits a hypoxic insult to RGCs, causing apoptosis via JNK-JUN signaling. The importance of EDN-induced vasoconstriction and hypoxia in causing RGC death after EDN insult and in models of glaucoma requires further investigation.

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Role of Main RNA Methylation in Hepatocellular Carcinoma: N6-Methyladenosine, 5-Methylcytosine, and N1-Methyladenosine

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.767668 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yating Xu ◽

Menggang Zhang ◽

Qiyao Zhang ◽

Xiao Yu ◽

Zongzong Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cellular Differentiation ◽

Molecular Mechanisms ◽

Gene Sequence ◽

Epigenetic Modification ◽

Biological Processes ◽

Biological Functions ◽

Rna Detection ◽

Rna Methylation

RNA methylation is considered a significant epigenetic modification, a process that does not alter gene sequence but may play a necessary role in multiple biological processes, such as gene expression, genome editing, and cellular differentiation. With advances in RNA detection, various forms of RNA methylation can be found, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 5-methylcytosine (m5C). Emerging reports confirm that dysregulation of RNA methylation gives rise to a variety of human diseases, particularly hepatocellular carcinoma. We will summarize essential regulators of RNA methylation and biological functions of these modifications in coding and noncoding RNAs. In conclusion, we highlight complex molecular mechanisms of m6A, m5C, and m1A associated with hepatocellular carcinoma and hope this review might provide therapeutic potent of RNA methylation to clinical research.

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Insights in the molecular mechanisms of an azole stress adapted laboratory-generated Aspergillus fumigatus strain

Medical Mycology ◽

10.1093/mmy/myaa118 ◽

2021 ◽

Author(s):

Marion Aruanno ◽

Samantha Gozel ◽

Isabelle Mouyna ◽

Josie E Parker ◽

Daniel Bachmann ◽

...

Keyword(s):

Transcription Factor ◽

Aspergillus Fumigatus ◽

Molecular Mechanisms ◽

Drug Transporters ◽

Major Facilitator Superfamily ◽

Ergosterol Biosynthesis ◽

Azole Resistance ◽

Drug Transporter

Abstract Aspergillus fumigatus is the main cause of invasive aspergillosis, for which azole drugs are the first-line therapy. Emergence of pan-azole resistance among A. fumigatus is concerning and has been mainly attributed to mutations in the target gene (cyp51A). However, azole resistance may also result from other mutations (hmg1, hapE) or other adaptive mechanisms. We performed microevolution experiment exposing an A. fumigatus azole-susceptible strain (Ku80) to sub-minimal inhibitory concentration of voriconazole to analyze emergence of azole resistance. We obtained a strain with pan-azole resistance (Ku80R), which was partially reversible after drug relief, and without mutations in cyp51A, hmg1, and hapE. Transcriptomic analyses revealed overexpression of the transcription factor asg1, several ATP-binding cassette (ABC) and major facilitator superfamily transporters and genes of the ergosterol biosynthesis pathway in Ku80R. Sterol analysis showed a significant decrease of the ergosterol mass under voriconazole exposure in Ku80, but not in Ku80R. However, the proportion of the sterol compounds was similar between both strains. To further assess the role of transporters, we used the ABC transporter inhibitor milbemycine oxime (MLB). MLB inhibited transporter activity in both Ku80 and Ku80R and demonstrated some potentiating effect on azole activity. Criteria for synergism were reached for MLB and posaconazole against Ku80. Finally, deletion of asg1 revealed some role of this transcription factor in controlling drug transporter expression, but had no impact on azole susceptibility. This work provides further insight in mechanisms of azole stress adaptation and suggests that drug transporters inhibition may represent a novel therapeutic target. Lay Summary A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

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Identification and characterization of the bZIP transcription factor family in yellowhorn

Journal of Forestry Research ◽

10.1007/s11676-020-01129-3 ◽

2020 ◽

Vol 32 (1) ◽

pp. 273-284 ◽

Cited By ~ 1

Author(s):

Qiaoying Chang ◽

Xin Lu ◽

Zhi Liu ◽

Zhimin Zheng ◽

Song Yu

Keyword(s):

Transcription Factor ◽

Leucine Zipper ◽

Molecular Mechanisms ◽

Bzip Transcription Factor ◽

Biological Functions ◽

Transcription Factor Family ◽

Promoter Regions ◽

Basic Leucine Zipper ◽

Biotic Stresses ◽

Bzip Transcription Factor Family

AbstractThe basic leucine zipper (bZIP) transcription factor family is one of the largest and most diverse families in plants, regulating plant growth and development and playing an essential role in response to abiotic and biotic stresses. However, little is known about the biological functions of bZIP proteins in yellowhorn (Xanthoceras sorbifolium). Recently, 64 XsbZIP genes were identified in the yellowhorn genome and found to be disproportionately distributed in linkage groups. The XsbZIP proteins clustered into 11 groups based on their phylogenetic relationships with AtbZIP, ZmbZIP and GmbZIP proteins. Five intron patterns in the basic and hinge regions and additional conserved motifs were defined, both supporting the group classification and possibly contributing to their functional diversity. Compared to tandem duplication, the segment duplication greatly contributed to the expansion of yellowhorn bZIP genes. In addition, most XsbZIP genes harbor several stress responsive cis-elements in their promoter regions. Moreover, the RNA-seq and qRT-PCR data indicated XsbZIP genes were extensively involved in response to various stresses, including salt (NaCl), cold and abscisic acid, with possibly different molecular mechanisms. These results provide a new understanding of the biological functions of bZIP transcription factors in yellowhorn.

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Mitochondrial Iron in Human Health and Disease

Annual Review of Physiology ◽

10.1146/annurev-physiol-020518-114742 ◽

2019 ◽

Vol 81 (1) ◽

pp. 453-482 ◽

Cited By ~ 14

Author(s):

Diane M. Ward ◽

Suzanne M. Cloonan

Keyword(s):

Human Health ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Innate Immune ◽

Biological Functions ◽

Mitochondrial Homeostasis ◽

Innate Immune Signaling ◽

Mitochondrial Iron ◽

Health And Disease

Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

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Progranulin modulates cartilage-specific gene expression via sirtuin 1–mediated deacetylation of the transcription factors SOX9 and P65

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011164 ◽

2020 ◽

Vol 295 (39) ◽

pp. 13640-13650 ◽

Cited By ~ 1

Author(s):

Dongxu Feng ◽

Xiaomin Kang ◽

Ruiqi Wang ◽

He Chen ◽

Kun Zhang ◽

...

Keyword(s):

Transcription Factor ◽

Molecular Mechanisms ◽

Sirtuin 1 ◽

Cartilage Tissue ◽

Nuclear Accumulation ◽

Specific Gene ◽

Causative Role ◽

Human Cartilage ◽

Cartilage Homeostasis

Progranulin (PGRN) is an autocrine growth factor that exerts crucial roles within cartilage tissue; however, the molecular mechanisms underlying PGRN-mediated cartilage homeostasis remain elusive. In the present study, we investigated the role of PGRN in regulating chondrocyte homeostasis and its therapeutic potential for managing osteoarthritis (OA). We found that PGRN levels are significantly increased in human cartilage in mild OA and that its expression is decreased in the cartilage in severe OA. In vitro, treatment of primary rat chondrocytes with recombinant PGRN significantly enhanced the levels of collagen type II α 1 chain (COL2A1) and aggrecan, and attenuated TNFα-induced up-regulation of matrix metallopeptidase 13 (MMP13) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5) in chondrocytes. These effects were abrogated in SIRT1−/− cells, indicating a causative role of SIRT1 in the effects of PGRN on protein expression in chondrocytes. Mechanistically, PGRN increased SIRT1 expression and activity, which reduced the acetylation levels of SRY-box transcription factor (SOX9) and transcription factor P65 (P65) and thereby promoted nuclear translocation of SOX9 and inhibited TNFα-induced P65 nuclear accumulation to maintain chondrocyte homeostasis. In conclusion, our findings reveal a mechanism of action for PGRN that maintains cartilage homeostasis and supports the notion that PGRN up-regulation may be a promising strategy for managing OA.

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A CCAAT/Enhancer Binding Protein β Isoform, Liver-Enriched Inhibitory Protein, Regulates Commitment of Osteoblasts and Adipocytes

Molecular and Cellular Biology ◽

10.1128/mcb.25.5.1971-1979.2005 ◽

2005 ◽

Vol 25 (5) ◽

pp. 1971-1979 ◽

Cited By ~ 64

Author(s):

Kenji Hata ◽

Riko Nishimura ◽

Mio Ueda ◽

Fumiyo Ikeda ◽

Takuma Matsubara ◽

...

Keyword(s):

Transcription Factor ◽

Osteoblast Differentiation ◽

Molecular Mechanisms ◽

Binding Protein ◽

Mesenchymal Cells ◽

Dominant Negative ◽

Inhibitory Protein ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein

ABSTRACT Although both osteoblasts and adipocytes have a common origin, i.e., mesenchymal cells, the molecular mechanisms that define the direction of two different lineages are presently unknown. In this study, we investigated the role of a transcription factor, CCAAT/enhancer binding protein β (C/EBPβ), and its isoform in the regulation of balance between osteoblast and adipocyte differentiation. We found that C/EBPβ, which is induced along with osteoblast differentiation, promotes the differentiation of mesenchymal cells into an osteoblast lineage in cooperation with Runx2, an essential transcription factor for osteogenesis. Surprisingly, an isoform of C/EBPβ, liver-enriched inhibitory protein (LIP), which lacks the transcriptional activation domain, stimulates transcriptional activity and the osteogenic action of Runx2, although LIP inhibits adipogenesis in a dominant-negative fashion. Furthermore, LIP physically associates with Runx2 and binds to the C/EBP binding element present in the osteocalcin gene promoter. These data indicate that LIP functions as a coactivator for Runx2 and preferentially promotes the osteoblast differentiation of mesenchymal cells. Thus, identification of a novel role of the C/EBPβ isoform provides insight into the molecular basis of the regulation of osteoblast and adipocyte commitment.

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