A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage‐specific genes in human chondrocytes

Hong, Seok Il; Derfoul, Assia; Mouriès, Lucilia Pereira; Hall, D.

doi:10.1096/fj.09-133215

Cited by 97 publications

(103 citation statements)

References 41 publications

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“…27 The expression of HDAC4 was increased in OA chondrocytes, whereas knockdown of HDAC4 attenuated the induction of catabolic gene expression in chondrocytes. 28 In another study, direct correlation was observed in the enhanced expression of MMP-13 and increased HDAC7 levels in OA cartilage.…”

Section: Discussionmentioning

confidence: 93%

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Makki

Haqqi

2016

The American Journal of Pathology

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Osteoarthritis (OA) is the most common whole-joint disease and is characterized by progressive loss of the cartilage matrix. Matrix metallopeptidase-13 (MMP-13) is a highly active and an abundantly expressed protease in OA cartilage and chondrocytes and degrades type II collagen and proteoglycans. We investigated the mechanism of MMP-13 suppression by histone deacetylase inhibitor vorinostat (SAHA). OA chondrocytes were obtained from knee cartilage after enzymatic digestion and treated with IL-1b in the absence or presence of various histone deacetylase inhibitors. Gene expression was quantified using quantitative RT-PCR. Protein expression and chromatin modifications were determined by Western immunoblotting using specific antibodies. The effect of IL-6 on the expression of MMP-13 was determined by treating chondrocytes with recombinant IL-6 or by IL6 knockdown using IL6-specific siRNA. We found that SAHA is a potent suppressor of IL-1beinduced MMP-13, tumor necrosis factor-a, and other catabolic marker expression in OA chondrocytes. Interestingly, SAHA rescued the COL2A1 and ACAN expression in OA chondrocytes that was down-regulated by IL-1b. Of importance is our finding that IL-6estimulated MMP-13 expression was independent of IL-1b stimulation and was blocked by SAHA, suggesting that SAHA inhibits IL-6 signaling in OA chondrocytes. Taken together, our results suggest that SAHA could be used as a therapeutic agent for the management of OA. (Am J Pathol 2016 http:// dx

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Section: Discussionmentioning

confidence: 93%

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Makki

Haqqi

2016

The American Journal of Pathology

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“…Chromatin modifications are one of the molecular mechanisms that mediate epigenetic regulation (43). Of them, HDACs, the chromatin-modifying enzymes, remove the acetyl groups, leading to chromatin condensation and repres- sion of transcription (44). A HDAC inhibitor also is involved in the expression of several genes.…”

Section: Results Of Immunostainingmentioning

confidence: 99%

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

Koike

Kasamatsu

Iyoda

et al. 2012

International Journal of Oncology

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Abstract.The four and a half LIM domains 1 (FHL1) gene has been related to carcinogenesis. However, the expression status of FHL1 in human oral squamous cell carcinoma (OSCC) remains unclear and the detailed mechanism of gene silencing is poorly understood. The aim of this study was to examine the FHL1 expression level and its regulatory mechanism in OSCCs. Quantitative reverse-transcriptase-polymerase chain reaction (PCR) and western blotting showed significant downregulation of FHL1 in all OSCC-derived cell lines (Sa3, HSC-2, HSC-3, HSC-4, HO-1-u-1, HO-1-N-1, KON and Ca9-22) compared to human normal oral keratinocytes. We also found that FHL1 mRNA expression was frequently downregulated (P<0.01) in 51 (86.4%) of 59 primary OSCCs compared with the corresponding normal oral tissues, while there was no significant difference between the status of the FHL1 protein expression in OSCCs and the clinicopathological features. Using methylationspecific PCR, we detected methylated FHL1 in all cell lines and treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine restored the FHL1 expression. However, no significant restoration of FHL1 expression was observed using sodium butyrate, an inhibitor of histone deacetylase and chromatin immunoprecipitation showed that histone H3 lysine 9 in the FHL1 promoter region was significantly acetylated. In addition, no mutation in the entire coding region of the FHL1 gene was found. Therefore, our data suggested that inactivation of the FHL1 gene is a frequent event during oral carcinogenesis and that the mechanism of FHL1 downregulation in OSCCs is through DNA methylation of the promoter region rather than histone deacetylation or mutation. IntroductionHead and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring malignancies and a major cause of morbidity and mortality (1,2). Oral cancer is the most common among the HNSCCs and the most frequently occurring oral cancer is squamous cell carcinoma (OSCC), which accounts for more than 90% of all oral malignancies (3). The number of OSCC cases that occur worldwide annually exceeds 300,000 (4). The mechanisms behind tumor progression of OSCC are known to a limited extent, indicating a clear need for comprehensive knowledge that can lead to more specific and effective molecular target.Microarray technology facilitates simultaneous evaluation of thousands of genes in a specimen. The results of microarray analysis provide researchers with high throughput screening to study the roles played by specific genes in cancer development and progression. We previously reported gene expression profiling of OSCC to identify cancer-related genes (5,6).The four and a half LIM domains (FHL) family of genes is characterized by LIM domains, a term derived from the first letters of three transcription factors: Lin-11, Isl-1 and Mec-3. Because the LIM domains provide protein-protein binding interfaces, the FHL genes play an important role in cellular events such as focal adhesion and differentiation by repressing or ac...

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“…Moreover, inhibition of histone deacetylases (HDACs) stimulates expression of SOX9-activated cartilage ECM genes and induces histone acetylation in the region of the Col2a1 enhancer in primary chondrocyte cultures (Furumatsu et al 2005). Overexpression of HDAC1 or 2 in chondrocytes results in down-regulation of expression of Aggrecan and Col2a1, providing further evidence for epigenetic control of this aspect of chondrocyte function (Hong et al 2009). …”

Section: Extracellular Matrixmentioning

confidence: 90%

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

Mackie¹,

Tatarczuch²,

Mirams³

2011

Journal of Endocrinology

368

319

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Endochondral ossification is the process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved. Chondrocytes play a central role in this process, contributing to longitudinal growth through a combination of proliferation, extracellular matrix (ECM) secretion and hypertrophy. Terminally differentiated hypertrophic chondrocytes then die, allowing the invasion of a mixture of cells that collectively replace the cartilage tissue with bone tissue. The behaviour of growth plate chondrocytes is tightly regulated at all stages of endochondral ossification by a complex network of interactions between circulating hormones (including GH and thyroid hormone), locally produced growth factors (including Indian hedgehog, WNTs, bone morphogenetic proteins and fibroblast growth factors) and the components of the ECM secreted by the chondrocytes (including collagens, proteoglycans, thrombospondins and matrilins). In turn, chondrocytes secrete factors that regulate the behaviour of the invading bone cells, including vascular endothelial growth factor and receptor activator of NFkB ligand. This review discusses how the growth plate chondrocyte contributes to endochondral ossification, with some emphasis on recent advances.

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A novel domain in histone deacetylase 1 and 2 mediates repression of cartilage‐specific genes in human chondrocytes

Cited by 97 publications

References 41 publications

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

Histone Deacetylase Inhibitor Vorinostat (SAHA) Suppresses IL-1β–Induced Matrix Metallopeptidase-13 Expression by Inhibiting IL-6 in Osteoarthritis Chondrocyte

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

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