High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma

Hebert, Carla; Norris, Kathleen; Scheper, Mark A.; Nikitakis, Nikolaos G.; Sauk, John J.

doi:10.1186/1476-4598-6-5

Cited by 252 publications

(107 citation statements)

References 41 publications

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“…This RNA has 13 binding sites for chondrocytic miRNAs in the 3Ј untranslated region (data not shown). This result is consistent with recent reports that let-7 and miR-98 suppress Hmga2 expression (30)(31)(32) by destabilizing its RNA (31).…”

Section: Discussionsupporting

confidence: 83%

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Kobayashi

Lü

Cobb

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

310

291

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Small noncoding RNAs, microRNAs (miRNAs), bind to messenger RNAs through base pairing to suppress gene expression. Despite accumulating evidence that miRNAs play critical roles in various biological processes across diverse organisms, their roles in mammalian skeletal development have not been demonstrated. Here, we show that Dicer, an essential component for biogenesis of miRNAs, is essential for normal skeletal development. Dicer-null growth plates show a progressive reduction in the proliferating pool of chondrocytes, leading to severe skeletal growth defects and premature death of mice. The reduction of proliferating chondrocytes in Dicer-null growth plates is caused by two distinct mechanisms: decreased chondrocyte proliferation and accelerated differentiation into postmitotic hypertrophic chondrocytes. These defects appear to be caused by mechanisms downstream or independent of the Ihh-PTHrP signaling pathway, a pivotal signaling system that regulates chondrocyte proliferation and differentiation. Microarray analysis of Dicer-null chondrocytes showed limited expression changes in miRNA-target genes, suggesting that, in the majority of cases, chondrocytic miRNAs do not directly regulate target RNA abundance. Our results demonstrate the critical role of the Dicer-dependent pathway in the regulation of chondrocyte proliferation and differentiation during skeletal development.microRNA ͉ skeletal development E ndochondral bone development is composed of the initial formation of a cartilage template and its subsequent replacement by mineralized bone. Longitudinal bone growth is driven by regulated proliferation and differentiation of chondrocytes in the growth plate cartilage. In developing growth plates, periarticular chondrocytes proliferate and differentiate into flat columnar chondrocytes that proliferate further to form orderly columns. Columnar chondrocytes stop proliferating and then differentiate into postmitotic hypertrophic chondrocytes. This process is tightly controlled by multiple layers of regulatory mechanisms, thus allowing persistent longitudinal bone growth.Regulation of gene expression is the major mechanism to control a variety of cellular functions, including proliferation and differentiation. Small noncoding microRNAs (miRNAs) encoded in the genome regulate gene expression at the posttranscriptional level. Genetic ablation of miRNA genes has demonstrated that loss of single miRNAs can results in significant physiological consequences in mice (1-4). In addition, germ-line ablation of genes encoding components for miRNA biogenesis results in embryonic or perinatal lethality in mice (5-7). These examples suggest that posttranscriptional gene regulation by miRNAs plays a critical role in regulating fundamental cellular functions in mice. miRNAs are generated from long primary transcripts (primiRNAs) through multiple processing steps (8). primiRNAs are cleaved into small-hairpin premiRNAs by the microprocessor complex containing Drosha and DGCR8. premiRNAs are exported into the cytoplasm, where ...

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Section: Discussionsupporting

confidence: 83%

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Kobayashi

Lü

Cobb

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

310

291

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“…HMGA2 is the downstream target of the let-7 family (37,46,47,60). The human let-7 family contains 13 members, including let-7a-1, let-7a-2, let-7a-3, let-7b, let-7c, let-7d, let-7e, let-7f-1, let7f-2, let-7g, let-7i, miR-98, and miR-202 (61).…”

Section: Discussionmentioning

confidence: 99%

“…8D). The HMGA2 3= UTR carries seven highly conserved let-7 binding sites; let-7 family members directly bind the 3= UTR and negatively regulate its expression (37,46,47). Using luciferase reporter plasmids carrying the wild-type HMGA2 3= UTR, transfection of cells with let-7 and miR-98 repressed reporter activity.…”

Section: Hdac10 Regulates Tumor Cell Proliferation In Vitro and In Vivomentioning

confidence: 99%

Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

Peng

Seto

2015

Molecular and Cellular Biology

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Histone deacetylase (HDAC) inhibition leads to cell cycle arrest in G 1 and G 2 , suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G 2 /M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation. Histone function is modulated by several posttranslational modifications, including reversible acetylation of the N-terminal ε-group of lysines on histones (1). Histone acetylation is tightly controlled by a balance between the opposing activities of histone acetyltransferases and histone deacetylases (HDACs). Acetylation of histone core molecules modulates chromatin structure and gene expression (2). The human HDAC family includes 18 members grouped into four classes. Class I HDACs, orthologs of Saccharomyces cerevisiae RPD3, are comprised of HDAC1, -2, -3, and -8. Class II, similar to yeast HDA1, has two subclasses: IIa (HDAC4, -5, -6, -7, and -9) and IIb (HDAC6 and -10). Class III, related to yeast SIR2, consists of seven sirtuins, which require NAD ϩ for activity. Class IV contains only HDAC11, which shows limited homologies to class I and II enzymes. Whereas class III HDACs are inhibited by nicotinamide, class I and II HDACs are dependent on Zn 2ϩ for deacetylase activity. The class IIb HDAC6 and HDAC10 are specifically sensitive to hydroxamate-type inhibitors (3), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Most hydroxamate inhibitors are nonselective, with the exception of tubacin and tabastatin A, which are selective for HDAC6 (4, 5). Another hydroxamate compound, bufexamac, also has been identified as a novel class IIb inhibitor that specifically inhibits HDAC6 at lower doses (3, 6). In addition, the cellular acetylome regulated by HDAC6 correlated with the profile observed after bufexamac treatment (6). However, the effect and mechanism of bufexamac on HDAC10 have not yet been well-studied. Thus, identification of the catalytic structure and mechanism of action of HDAC10 might inform the development of a selective inhibitor in future research.HDACs play important roles in the regulation of the cell cycle, apoptosis, stress responses, and DNA repair, indicating that they are key regulators of normal ...

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“…miRNAs have been shown to play important roles in regulating a broad range of pathological processes. Over the past few years, many tumor suppressor genes (TSGs) and oncogenes have been demonstrated to be regulated by miRNAs, with these miRNAs therefore acting as oncogenes or TSGs themselves [7][8][9] to regulate cancer cell survival and proliferation. The critical roles of miRNAs in modulating cancer cell response to chemotherapeutic agents have also been documented.…”

Section: Introductionmentioning

confidence: 99%

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel

Borkowski

Zhao

et al. 2013

RNA Biology

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microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR-346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications.

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High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma

Cited by 252 publications

References 41 publications

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel

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High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma

Cited by 252 publications

References 41 publications

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Dicer-dependent pathways regulate chondrocyte proliferation and differentiation

Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel

Contact Info

Product

Resources

About

Histone Deacetylase 10 Regulates the Cell Cycle G₂/M Phase Transition via a Novel Let-7–HMGA2–Cyclin A2 Pathway