In vivo modulation of HMGA2 expression

Ashar, Hena R.; Chouinard, Roland A.; Dokur, Madhavi; Chada, Kiran

doi:10.1016/j.bbagrm.2009.11.013

Cited by 46 publications

(42 citation statements)

References 31 publications

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“…HMG proteins modulate gene expression by altering chromatin architecture and/or recruiting other proteins to the transcription regulatory complex (55). HMGA2 is highly expressed in various undifferentiated tissues during embryonic development, and expression is also elevated in a variety of cancer cells, implying that HMGA2 plays a role in controlling proliferation and differentiation (56)(57)(58). Furthermore, HMGA2 was shown to activate the cyclin A2 promoter by counteracting the repressive activity of p120 E4F via the ATF/CRE site (34).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…38 HMGA2 protein is abundant in pluripotent embryonic stem cells and has been reported to play an important role in pituitary adenomas formation.…”

Section: Discussionmentioning

confidence: 99%

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

Yang

Zhang

Zhao

et al. 2015

Cancer Biology & Therapy

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Background: Lung cancer is the most common cancer that is caused by perturbation of regulatory pathways rather than dysfunction of a single gene. Cisplatin (CDDP; cis-diamminedichloroplatinum II) is the first member of a class of platinum-containing anti-cancer medication, which binds to DNA and triggers apoptosis. CDDP-based chemotherapy is used to treat various types of cancers. However, the efficacy of CDDP in the treatment of non-small-cell lung cancer (NSCLC) is limited by acquired drug resistance. MicroRNAs have recently emerged as key regulators of cancers, and miR-26a is one of downregulated miRNAs in A549/CDDP res cell line. This study aimed to investigate the role of miR-26a in CDDP resistance in NSCLC as well as the underlying mechanisms.Methods: In this study, we analyzed expressional profiles of CDDP resistance-related mRNA, miRNA, and transcription factors (TF) that regulate miRNA expression in NSCLC. A549 cells were treated with CDDP, miR-26a mimic, or miR-26a inhibitor, and followed by biological analysis including drug sensitivity assay, colony formation assay, terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay, and cell cycle analysis. Luciferase assay was used to determine the target of miR-26a. The regulation of miR-26a in Akt pathway was measured by western blot.Results: High mobility group A (HMGA) 2 was identified as the target of miR-26a. Overexpression of miR26a in A549 cells inhibited G1-S transition, increased cell death in response to CDDP treatment, and decreased the colony formation of A549 cells. MiR-26a significantly decreased the expression of E2F1, diminished Akt phosphorylation, and downregulated Bcl2 expression. Cell growth was suppressed by inhibiting HMGA2-mediated E2F1-Akt pathway.Conclusion: MiR-26a is responsible for A549 cell sensitivity in the treatment of CDDP through regulating HMGA2-mediated E2F1-Akt pathway.

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“…The DNA architectural factor and protooncogene Hmga2 is often overexpressed in tumor cells. HMGA2 directly interacts with chromatin and facilitates RNA transcription (34). The Hmaga2 gene, predicted to have six conserved let-7 binding sites, is one of the bestcharacterized let-7 target genes.…”

Section: Lin28a Overexpression In Chondrocytes Reduces Proliferation Andmentioning

confidence: 99%

let-7 and miR-140 microRNAs coordinately regulate skeletal development

Papaioannou

Inloes

Nakamura

et al. 2013

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

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Significance A global reduction of microRNAs (miRNAs) in growth plate chondrocytes results in defects in both proliferation and differentiation; however, specific miRNAs that regulate these processes have not been identified. In this study, we provide evidence that let-7 miRNAs and microRNA-140 (miR-140), among other miRNAs, play major roles in endochondral bone development. We found that suppression of let-7 miRNAs in chondrocytes reduced proliferation, whereas the chondrocyte-specific miR-140 was necessary for differentiation into proliferating chondrocytes. Deficiency of both let-7 and miR-140 caused a dramatic growth defect, synergistically reducing proliferating chondrocyte mass. Thus, these miRNAs coordinately regulate distinct steps of endochondral bone development.

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In vivo modulation of HMGA2 expression

Cited by 46 publications

References 31 publications

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

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

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

let-7 and miR-140 microRNAs coordinately regulate skeletal development

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In vivo modulation of HMGA2 expression

Cited by 46 publications

References 31 publications

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

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

Decreased MicroRNA-26a expression causes cisplatin resistance in human non-small cell lung cancer

let-7 and miR-140 microRNAs coordinately regulate skeletal development

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

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