Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

Sampath, Deepa; Liu, Chaomei; Vasan, Karthik; Sulda, Melanie; Puduvalli, Vinay K.; Wierda, William G.; Keating, Michael J.

doi:10.1182/blood-2011-05-351510

Cited by 182 publications

(152 citation statements)

References 48 publications

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“…Emerging evidence has proven that HDAC4 signaling regulates miR-mediated somatic cell reprogramming 37 and keratinocyte senescence, 38 as well as represses the miR-29b action in chronic lymphocytic leukemia. 39 It is noteworthy that this study revealed that HDAC4 interruption restored H3K9Ac enrichment in the miR-29a promoter region and increased miR-29a transcription in high glucose-stressed podocyte cultures. The experimental results provide a new perspective that HDAC4 via an epigenetic pathway represses miR-29a transcription in the progression of high glucose-induced podocyte injury.…”

Section: Discussionmentioning

confidence: 96%

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Lin

Lee

Hsu

et al. 2014

Journal of the American Society of Nephrology

163

156

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Podocyte dysfunction is a detrimental feature in diabetic nephropathy, with loss of nephrin integrity contributing to diabetic podocytopathy. MicroRNAs (miRs) reportedly modulate the hyperglycemiainduced perturbation of renal tissue homeostasis. This study investigated whether regulation of histone deacetylase (HDAC) actions and nephrin acetylation by miR-29 contributes to podocyte homeostasis and renal function in diabetic kidneys. Hyperglycemia accelerated podocyte injury and reduced nephrin, acetylated nephrin, and miR-29a levels in primary renal glomeruli from streptozotocin-induced diabetic mice. Diabetic miR-29a transgenic mice had better nephrin levels, podocyte viability, and renal function and less glomerular fibrosis and inflammation reaction compared with diabetic wild-type mice. Overexpression of miR-29a attenuated the promotion of HDAC4 signaling, nephrin ubiquitination, and urinary nephrin excretion associated with diabetes and restored nephrin acetylation. Knockdown of miR-29a by antisense oligonucleotides promoted HDAC4 action, nephrin loss, podocyte apoptosis, and proteinuria in nondiabetic mice. In vitro, interruption of HDAC4 signaling alleviated the high glucose-induced apoptosis and inhibition of nephrin acetylation in podocyte cultures. Furthermore, HDAC4 interference increased the acetylation status of histone H3 at lysine 9 (H3K9Ac), the enrichment of H3K9Ac in miR-29a proximal promoter, and miR-29a transcription in high glucose-stressed podocytes. In conclusion, hyperglycemia impairs miR-29a signaling to intensify HDAC4 actions that contribute to podocyte protein deacetylation and degradation as well as renal dysfunction. HDAC4, via epigenetic H3K9 hypoacetylation, reduces miR29a transcription. The renoprotective effects of miR-29a in diabetes-induced loss of podocyte integrity and renal homeostasis highlights the importance of post-translational acetylation reactions in podocyte microenvironments. Increasing miR-29a action may protect against diabetic podocytopathy.

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Section: Discussionmentioning

confidence: 96%

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Lin

Lee

Hsu

et al. 2014

Journal of the American Society of Nephrology

163

156

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“…ChIP analysis GH3 cell again showed histone modifications similar to those apparent in primary human pituitary adenoma. Since we [19,41] and others [18,[42][43][44] have used epidrugs to restore expression of endogenous, epigenetically silenced mRNA and that of miRNA respectively, we exploited this approach in this report. For the first time, in a pituitary context we found combined drug challenges induced expression of the miRNA.…”

Section: Discussionmentioning

confidence: 99%

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

et al. 2015

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“…17 Expression and Functions of miR-15/16 in CLL Since our initial observation that miR-15/16 is deleted or downregulated in two-thirds of CLL samples, several other studies confirmed our results. 18,19 Tumor-suppressor genes in cancer are also frequent targets of mutations that can inactivate their function, and finding such mutations is a critical step in determining the contribution of microRNA or mRNA gene(s) in hematopoietic or solid malignancies. As miR-15/16 is a target of 13q14 deletions in CLL, it is possible that mutations could have a role in inactivation of its expression.…”

Section: Mir-15/16 At 13q14 Gene Discoverymentioning

confidence: 99%

Role of miR-15/16 in CLL

2014

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B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The most common chromosomal abnormalities detectable by cytogenetics include deletion at 13q (55%), 11q (18%), trisomy 12 (12-16%) and 17p (8%). In 2002, we discovered that a microRNA cluster miR-15a/miR-16-1 (miR-15/16) is the target of 13q deletions in CLL. MicroRNAs encoded by the miR-15/16 locus (miR-15 and miR-16) function as tumor suppressors. Expression of these miRNAs downregulated in CLL, melanoma, colorectal cancer, bladder cancer and other solid tumors. miR-15/16 cluster targets multiple oncogenes, including BCL2, Cyclin D1, MCL1 and others. The most important target of miR-15/16 in CLL is arguably BCL2, as BCL2 is overexpressed in almost all CLLs. In this review, we discuss the discovery, functions, clinical relevance and treatment opportunities related to miR-15/16.

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Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia

Cited by 182 publications

References 48 publications

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

MicroRNA-29a Promotion of Nephrin Acetylation Ameliorates Hyperglycemia-Induced Podocyte Dysfunction

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

Role of miR-15/16 in CLL

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