TP53-independent Function of miR-34a via HDAC1 and p21CIP1/WAF1

Zhao, Jane; Lammers, Paul; Torrance, Chris; Bader, Andreas G.

doi:10.1038/mt.2013.148

Cited by 55 publications

(47 citation statements)

References 40 publications

(61 reference statements)

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“…miR-34a is often found inactivated in cancer cells (10). It has been reported that inhibition of HDAC1 mimics the miR-34a phenotype (22). In the present study, we have further demonstrated that depletion of HDAC1 upregulated the expression of miR-34a, but had little effect on the expression of miR-34b or miR34c, suggesting that overexpressed HDAC1 exerts its actions on gastric cancer cells by dysregulating miR-34a.…”

Section: Discussionsupporting

confidence: 73%

“…In accordance, in the present study we have shown that depletion of HDAC1 by siRNA resulted in an altered expression of 101 differentially expressed miRNAs matching the 4-fold threshold in gastric cancer cells. miR-34, a transcriptional target of p53, is a potent tumor suppressor that inhibits a broad range of cancer cells by repressing a plethora of oncogenes that control cell proliferation, senescence, apoptosis and metastasis (10,22). The miR-34 family comprises three processed miRNAs that are encoded by two different genes: miR-34a is encoded by its own transcript, whereas miR-34b and miR-34c share a common primary transcript (10).…”

Section: Discussionmentioning

confidence: 99%

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Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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Abstract. Overexpression of histone deacetylases (HDACs) is associated with higher metastatic rates and a poor prognosis in gastric cancer. However, the underlying mechanisms involved remain unclear. The present study aimed to investigate the molecular pathways that are involved in HDAC1-mediated metastatic activities in gastric cancer cells. First we used a microRNA (miRNA or miR) microarray to screen potential miRNAs whose expression can be altered by HDAC1 depletion. Of these miRNAs, miR-34a is important as it is often inactivated in cancer cells and acts as a tumor suppressor for various types of cancer. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results confirmed that miR-34a was upregulated by HDAC1 knockdown. Cells depleted of HDAC1 had lower abilities to migrate, invade and adhere, which were restored by a miR-34a antagomiR. Depletion of HDAC1 also resulted in impaired microfilaments and microtubules, while co-transfection of the miR-34a antagomiR attenuated these changes in the cellular cytoskeleton. The HDAC1/miR-34a axis regulated the expression and activation of CD44 and its downstream factors including Bcl-2, Ras homolog family member A (RhoA), LIM domain kinase 1 (LIMK-1) and matrix metalloproteinase (MMP)-2. The latter three proteins were responsible for the organization of tubulin and actin cytoskeleton and the formation of cellular pseudopodia. In conclusion, results of the present study indicated that HDAC1 depletion inhibits the metastatic abilities of gastric cancer cells by regulating the miRNA-34a/CD44 pathway, which may be a potential target for the treatment of gastric cancer. IntroductionGastric cancer remains the fourth most common malignancy and the second leading cause of cancer-related mortality worldwide, although its incidence is gradually on the decrease in most parts of the world (1). The currently available chemotherapeutic agents have only limited benefits for most gastric cancer patients. Therefore, identification of novel targets and an understanding of their molecular mechanisms is crucial for the treatment of gastric cancer patients.Histone deacetylases (HDACs) are a class of enzymes that remove the acetyl groups from core histones, as well as non-histone proteins, such as p53 (2). By modifying the status of deacetylation, HDACs induce transcriptional repression through chromatin condensation and alteration of protein activity (3). Among the 18 HDAC family members, HDAC1 accounts for more than half of cellular HDAC activity, and cannot be compensated by other HDACs (4). HDAC1 acts at all levels of gene expression including microRNA (miRNA or miR) regulation (5). Overexpression of HDAC1 is significantly associated with higher lymphatic metastases and decreased 3-year survival rates in gastric cancer patients (6). Many HDAC inhibitors have been developed, several of which have shown promise and are under investigation in clinical trials (3,7). However, the underlying mechanisms for the anti-metastatic activities of HDAC inhibitors, particularly...

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

et al. 2015

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“…To gain additional evidence for an indirect mechanism of HbF regulation by miR-34a, we analyzed proteins known to be negative regulators of g-globin transcription and previously shown to be silenced by miR-34a including YY1, HDAC1, and STAT3. [32][33][34][35][36] YY1 binds the À1086 region in the upstream g-globin promoter to silence gene expression 55 ; by contrast, HDAC1 and HDAC2 are protein components of the nucleosome remodeling deacetylation complex 56 which plays a pivotal role in DNA methylation associated with globin silencing in b-YAC mice. 57 Histone deacetylase inhibitors such as sodium butyrate induce HbF 58 by inhibiting HDACs broadly producing histone hyperacetylation and a favorable open chromatin conformation to facilitate gene activation.…”

Section: Discussionmentioning

confidence: 99%

“…A wide variety of genes are targeted by miR-34a, 27,[30][31][32][33][34][35][36] including the known g-globin repressors YY1, HDAC1, and STAT3 among others. Therefore, we performed studies to determine whether miR34a indirectly regulates g-globin expression through one of these negative regulators.…”

Section: Mir34a Overexpression Silences Stat3 Gene Expressionmentioning

confidence: 99%

Original Research: Stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells

Ward

Pace

2016

Exp Biol Med (Maywood)

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Sickle cell anemia is a common genetic disorder caused by a point mutation in the sixth codon of the b-globin gene affecting people of African descent worldwide. A wide variety of clinical phenotypes ranging from mild to severe symptoms and complications occur due to hemoglobin S polymerization, red blood cell sickling, and vaso-occlusion. Research efforts are ongoing to develop strategies of fetal hemoglobin (HbF; a 2 g 2 ) induction to inhibit sickle hemoglobin polymerization and improve clinical outcomes. Insights have been gained from investigating mutations in the b-globin locus or transcription factors involved in the mechanisms of hemoglobin switching. Recent efforts to expand molecular targets that modulate g-globin expression involve microRNAs that work through posttranscriptional gene regulation. Therefore, the goal of our study was to identify novel microRNA genes involved in fetal hemoglobin expression. Using in silico analysis, we identified a miR-34a binding site in the g-globin mRNA which was tested for functional relevance. Stable expression of the shMIMIC miR-34a lentivirus vector increased fetal hemoglobin levels in single cell K562 clones consistent with silencing of a g-globin gene repressor. Furthermore, miR-34a promoted cell differentiation supported by increased expression of KLF1, glycophorin A, and the erythropoietin receptor. Western blot analysis of known negative regulators of g-globin including YY1, histone deacetylase 1, and STAT3, which are regulated by miR-34a showed no change in YY1 and histone deacetylase 1 levels; however, total-and phosphorylated-STAT3 levels were decreased in single cell miR-34a K562 clones. These data support a mechanism of fetal hemoglobin activation by miR-34a involving STAT3 gene silencing.

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“…Silencing of HDAC expression induces a G2/M growth arrest and stimulates p21 promoter activity in colon cancer cells (35). Although the cell cycle-dependent kinase inhibitor p21 is known to be transcriptionally regulated by p53, induction of p21 by HDAC inhibitors does not always require the presence of wild-type p53 (36). Both p53-dependent and p53-independent anticancer effects have also been demonstrated for HDAC inhibitors (37).…”

Section: Minmentioning

confidence: 99%

Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

Kanda¹,

Sakamoto

Matsumoto³

et al. 2018

JCI Insight

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TP53-independent Function of miR-34a via HDAC1 and p21CIP1/WAF1

Cited by 55 publications

References 40 publications

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway

Original Research: Stable expression of miR-34a mediates fetal hemoglobin induction in K562 cells

Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

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