Epi-miRNAs: Regulators of the Histone Modification Machinery in Human Cancer

Cancer is a leading cause of death and disability worldwide. Epigenetic deregulation is one of the most critical mechanisms in carcinogenesis and can be classified into effects on DNA methylation and histone modification. MicroRNAs are small noncoding RNAs involved in fine-tuning their target genes after transcription. Various microRNAs control the expression of histone modifiers and are involved in a variety of cancers. Therefore, overexpression or downregulation of microRNAs can alter cell fate and cause malignancies. In this review, we discuss the role of microRNAs in regulating the histone modification machinery in various cancers, with a focus on the histone-modifying enzymes such as acetylases, deacetylases, methyltransferases, demethylases, kinases, phosphatases, desumoylases, ubiquitinases, and deubiquitinases. Understanding of microRNA-related aberrations underlying histone modifiers in pathogenesis of different cancers can help identify novel therapeutic targets or early detection approaches that allow better management of patients or monitoring of treatment response.

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MicroRNAs’ Involvement in Osteoarthritis and the Prospects for Treatments

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/236179 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Xiao-Ming Yu ◽

Hao-Ye Meng ◽

Xue-Ling Yuan ◽

Yu Wang ◽

Quan-Yi Guo ◽

...

Keyword(s):

Molecular Mechanisms ◽

Target Genes ◽

Noncoding Rnas ◽

Genetic Changes ◽

Future Studies ◽

Small Noncoding Rnas ◽

Cartilage Homeostasis ◽

Target Binding ◽

And Cartilage

Osteoarthritis (OA) is a chronic disease and its etiology is complex. With increasing OA incidence, more and more people are facing heavy financial and social burdens from the disease. Genetics-related aspects of OA pathogenesis are not well understood. Recent reports have examined the molecular mechanisms and genes related to OA. It has been realized that genetic changes in articular cartilage and bone may contribute to OA’s development. Osteoclasts, osteoblasts, osteocytes, and chondrocytes in joints must express appropriate genes to achieve tissue homeostasis, and errors in this can cause OA. MicroRNAs (miRNAs) are small noncoding RNAs that have been discovered to be overarching regulators of gene expression. Their ability to repress many target genes and their target-binding specificity indicate a complex network of interactions, which is still being defined. Many studies have focused on the role of miRNAs in bone and cartilage and have identified numbers of miRNAs that play important roles in regulating bone and cartilage homeostasis. Those miRNAs may also be involved in the pathology of OA, which is the focus of this review. Future studies on the role of miRNAs in OA will provide important clues leading to a better understanding of the mechanism(s) of OA and, more particularly, to the development of therapeutic targets for OA.

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miR-30 Family: A Promising Regulator in Development and Disease

BioMed Research International ◽

10.1155/2018/9623412 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 21

Author(s):

Ling Mao ◽

Shiming Liu ◽

Lin Hu ◽

Li Jia ◽

Hairong Wang ◽

...

Keyword(s):

Target Genes ◽

Noncoding Rnas ◽

Small Noncoding Rnas ◽

Related Disease ◽

The Future

MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate posttranscriptional expression of target genes. Accumulating evidences have demonstrated that the miR-30 family, as a member of microRNAs, played a crucial regulating role in the development of tissues and organs and the pathogenesis of clinical diseases, which indicated that it may be a promising regulator in development and disease. This review aims to clarify the current progress on the regulating role of miR-30 family in tissues and organs development and related disease and highlight their research prospective in the future.

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The role of let-7 in cell differentiation and cancer

Endocrine Related Cancer ◽

10.1677/erc-09-0184 ◽

2010 ◽

Vol 17 (1) ◽

pp. F19-F36 ◽

Cited By ~ 435

Author(s):

Benjamin Boyerinas ◽

Sun-Mi Park ◽

Annika Hau ◽

Andrea E Murmann ◽

Marcus E Peter

Keyword(s):

Drug Sensitivity ◽

Normal Development ◽

Human Cancer ◽

Therapeutic Option ◽

Noncoding Rnas ◽

Current Evidence ◽

Small Noncoding Rnas ◽

Development And Differentiation ◽

The Relationship

MicroRNAs (miRNAs or miRs) are small noncoding RNAs capable of regulating gene expression at the translational level. Current evidence suggests that a significant portion of the human genome is regulated by microRNAs, and many reports have demonstrated that microRNA expression is deregulated in human cancer. The let-7 family of microRNAs, first discovered in Caenorhabditis elegans, is functionally conserved from worms to humans. The human let-7 family contains 13 members located on nine different chromosomes, and many human cancers have deregulated let-7 expression. A growing body of evidence suggests that restoration of let-7 expression may be a useful therapeutic option in cancers, where its expression has been lost. In this review, we discuss the role of let-7 in normal development and differentiation, and provide an overview of the relationship between deregulated let-7 expression and tumorigenesis. The regulation of let-7 expression, cancer-relevant let-7 targets, and the relationship between let-7 and drug sensitivity are highlighted.

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Roles of pRB in the Regulation of Nucleosome and Chromatin Structures

BioMed Research International ◽

10.1155/2016/5959721 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Chiharu Uchida

Keyword(s):

Target Genes ◽

Chromosome Instability ◽

Cancer Therapies ◽

Induce Cell Cycle Arrest ◽

Cellular Events ◽

Cycle Arrest ◽

Histone Modifiers ◽

Physical Interactions ◽

Functional Inactivation

Retinoblastoma protein (pRB) interacts with E2F and other protein factors to play a pivotal role in regulating the expression of target genes that induce cell cycle arrest, apoptosis, and differentiation. pRB controls the local promoter activity and has the ability to change the structure of nucleosomes and/or chromosomes via histone modification, epigenetic changes, chromatin remodeling, and chromosome organization. Functional inactivation of pRB perturbs these cellular events and causes dysregulated cell growth and chromosome instability, which are hallmarks of cancer cells. The role of pRB in regulation of nucleosome/chromatin structures has been shown to link to tumor suppression. This review focuses on the ability of pRB to control nucleosome/chromatin structures via physical interactions with histone modifiers and chromatin factors and describes cancer therapies based on targeting these protein factors.

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Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments

International Journal of Molecular Sciences ◽

10.3390/ijms22115711 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5711

Author(s):

Julian Zacharjasz ◽

Anna M. Mleczko ◽

Paweł Bąkowski ◽

Tomasz Piontek ◽

Kamilla Bąkowska-Żywicka

Keyword(s):

Knee Osteoarthritis ◽

Noncoding Rnas ◽

Pathological Process ◽

Joint Disease ◽

Limited Information ◽

Genetic Changes ◽

Small Noncoding Rnas ◽

Knee Oa ◽

Cartilage Homeostasis

Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world's population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis.

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Mitochondrial microRNAs: A Putative Role in Tissue Regeneration

Biology ◽

10.3390/biology9120486 ◽

2020 ◽

Vol 9 (12) ◽

pp. 486

Author(s):

Sílvia C. Rodrigues ◽

Renato M. S. Cardoso ◽

Filipe V. Duarte

Keyword(s):

Tissue Regeneration ◽

Protein Complexes ◽

Mitochondrial Protein ◽

Noncoding Rnas ◽

Atp Synthesis ◽

Mitochondrial Proteins ◽

Cellular Mechanisms ◽

Small Noncoding Rnas ◽

Mitochondrial Ribosome

The most famous role of mitochondria is to generate ATP through oxidative phosphorylation, a metabolic pathway that involves a chain of four protein complexes (the electron transport chain, ETC) that generates a proton-motive force that in turn drives the ATP synthesis by the Complex V (ATP synthase). An impressive number of more than 1000 mitochondrial proteins have been discovered. Since mitochondrial proteins have a dual genetic origin, it is predicted that ~99% of these proteins are nuclear-encoded and are synthesized in the cytoplasmatic compartment, being further imported through mitochondrial membrane transporters. The lasting 1% of mitochondrial proteins are encoded by the mitochondrial genome and synthesized by the mitochondrial ribosome (mitoribosome). As a result, an appropriate regulation of mitochondrial protein synthesis is absolutely required to achieve and maintain normal mitochondrial function. Regarding miRNAs in mitochondria, it is well-recognized nowadays that several cellular mechanisms involving mitochondria are regulated by many genetic players that originate from either nuclear- or mitochondrial-encoded small noncoding RNAs (sncRNAs). Growing evidence collected from whole genome and transcriptome sequencing highlight the role of distinct members of this class, from short interfering RNAs (siRNAs) to miRNAs and long noncoding RNAs (lncRNAs). Some of the mechanisms that have been shown to be modulated are the expression of mitochondrial proteins itself, as well as the more complex coordination of mitochondrial structure and dynamics with its function. We devote particular attention to the role of mitochondrial miRNAs and to their role in the modulation of several molecular processes that could ultimately contribute to tissue regeneration accomplishment.

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Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor

Blood ◽

10.1182/blood-2010-11-317800 ◽

2011 ◽

Vol 118 (4) ◽

pp. 1154-1162 ◽

Cited By ~ 73

Author(s):

Wei Zheng ◽

Tuomas Tammela ◽

Masahiro Yamamoto ◽

Andrey Anisimov ◽

Tanja Holopainen ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Target Genes ◽

Notch Pathway ◽

Lymphatic Vessels ◽

Soluble Form ◽

Fibrin Gel ◽

3 Dimensional ◽

Endothelial Growth Factor

Abstract Notch signaling plays a central role in cell-fate determination, and its role in lateral inhibition in angiogenic sprouting is well established. However, the role of Notch signaling in lymphangiogenesis, the growth of lymphatic vessels, is poorly understood. Here we demonstrate Notch pathway activity in lymphatic endothelial cells (LECs), as well as induction of delta-like ligand 4 (Dll4) and Notch target genes on stimulation with VEGF or VEGF-C. Suppression of Notch signaling by a soluble form of Dll4 (Dll4-Fc) synergized with VEGF in inducing LEC sprouting in 3-dimensional (3D) fibrin gel assays. Expression of Dll4-Fc in adult mouse ears promoted lymphangiogenesis, which was augmented by coexpressing VEGF. Lymphangiogenesis triggered by Notch inhibition was suppressed by a monoclonal VEGFR-2 Ab as well as soluble VEGF and VEGF-C/VEGF-D ligand traps. LECs transduced with Dll4 preferentially adopted the tip cell position over nontransduced cells in 3D sprouting assays, suggesting an analogous role for Dll4/Notch in lymphatic and blood vessel sprouting. These results indicate that the Notch pathway controls lymphatic endothelial quiescence, and explain why LECs are poorly responsive to VEGF compared with VEGF-C. Understanding the role of the Notch pathway in lymphangiogenesis provides further insight for the therapeutic manipulation of the lymphatic vessels.

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MicroRNA-Mediated Regulation in Biological Systems with Oscillatory Behavior

BioMed Research International ◽

10.1155/2013/285063 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Zhiyong Zhang ◽

Fengdan Xu ◽

Zengrong Liu ◽

Ruiqi Wang ◽

Tieqiao Wen

Keyword(s):

Cell Cycle ◽

Biological Systems ◽

Noncoding Rnas ◽

Oscillatory Behavior ◽

Fine Tuning ◽

Base Pairing ◽

Periodic Behavior ◽

Small Noncoding Rnas ◽

Regulatory Circuits ◽

Mrna Transcripts

As a class of small noncoding RNAs, microRNAs (miRNAs) regulate stability or translation of mRNA transcripts. Some reports bring new insights into possible roles of microRNAs in modulating cell cycle. In this paper, we focus on the mechanism and effectiveness of microRNA-mediated regulation in the cell cycle. We first describe two specific regulatory circuits that incorporate base-pairing microRNAs and show their fine-tuning roles in the modulation of periodic behavior. Furthermore, we analyze the effects ofmiR369-3on the modulation of the cell cycle, confirming thatmiR369-3plays a role in shortening the period of the cell cycle. These results are consistent with experimental observations.

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Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416287112 ◽

2015 ◽

Vol 112 (5) ◽

pp. E402-E409 ◽

Cited By ~ 70

Author(s):

Marcelo Boareto ◽

Mohit Kumar Jolly ◽

Mingyang Lu ◽

José N. Onuchic ◽

Cecilia Clementi ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Target Genes ◽

Tumor Stroma ◽

Notch Receptor ◽

Toggle Switch ◽

Cell Fate Determination ◽

Asymmetric Effect ◽

Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

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