Runx2 Recruits p300 to Mediate Parathyroid Hormone’s Effects on Histone Acetylation and Transcriptional Activation of the Matrix Metalloproteinase-13 Gene

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Background: Parathyroid hormone (PTH) stimulates MMP13 in osteoblasts. Results: Sirtuin 1 (SIRT1) activation suppresses PTH stimulation of Mmp13 expression, and this process is mediated by the AP-1 complex. Conclusion: SIRT1 is a novel suppressor of PTH stimulation of MMP13 expression. Significance: Activation of SIRT1 and suppression of MMP13 may prolong the anabolic bone-forming period of PTH treatment in osteoporotic patients.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Sirtuin 1 Is a Negative Regulator of Parathyroid Hormone Stimulation of Matrix Metalloproteinase 13 Expression in Osteoblastic Cells

Fei

Shimizu

McBurney³

et al. 2015

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“…At the MMP-13 promoter in osteoblastic cells, we have shown that Runx2 binds HDAC4, resulting in a repression of transcription under basal conditions (22). After PTH treatment, HDAC4 dissociates from Runx2, which is then free to recruit p300 to activate transcription (23).…”

Section: Pthmentioning

confidence: 98%

Parathyroid Hormone Activation of Matrix Metalloproteinase-13 Transcription Requires the Histone Acetyltransferase Activity of p300 and PCAF and p300-dependent Acetylation of PCAF

Lee

Partridge

2010

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Parathyroid hormone (PTH) regulates the transcription of many genes involved in bone remodeling in osteoblasts. One of these genes is matrix metalloproteinase-13 (MMP-13), which is involved in bone remodeling and early stages of endochondral bone formation. We have previously shown that Mmp-13 gene expression is highly induced by PTH treatment in osteoblastic UMR 106-01 cells, as well as primary osteoblasts. Here, we show that p300/CBP-associated factor (PCAF), in addition to p300 and Runx2, is required for PTH activation of Mmp-13 transcription. PCAF was increasingly recruited to the MMP-13 proximal promoter region after PTH treatment, and this was associated with an increase in RNA polymerase II recruitment and histone acetylation. In addition, PTH treatment increased the acetylation of PCAF, a process that required p300. Knockdown of PCAF, p300, or Runx2 by siRNA decreased Mmp-13 mRNA expression after PTH treatment in both UMR 106-01 cells and primary osteoblasts. We found that there is a mutual dependence between p300 and PCAF to be recruited to the Mmp-13 promoter after PTH treatment. In promoter-reporter assays, p300 and PCAF had an additive effect on PTH stimulation of MMP-13 promoter activity, and this required their histone acetyltransferase activity. Our findings demonstrate that PCAF acts downstream of PTH signaling as a transcriptional coactivator that is required for PTH stimulation of MMP-13 transcription. PCAF cooperates with p300 and Runx2 to mediate PTH activation of MMP-13 transcription. PTH2 is a peptide hormone that plays a central role in regulating serum ion concentrations. Secreted from the parathyroid glands in response to low serum calcium levels, PTH has two primary sites of action, bone and kidney. In bone, PTH stimulates the release of calcium and phosphate ions from the bone mineral matrix, leading to bone degradation such that PTH is classically known as a catabolic agent in bone remodeling.However, when administered intermittently, PTH has an anabolic effect that leads to increased bone mass. Binding of PTH to its receptor, PTH1R, on the surface of osteoblasts leads to the activation of many different signaling pathways, including protein kinase A (PKA)-and protein kinase C (PKC)-dependent pathways, as well as calcium ion channels (reviewed in Ref. 1). This eventually leads to a significant change in gene expression in osteoblasts (2). Microarray analyses from our laboratory demonstrated that the catabolic effect of PTH on bone predominantly occurs through PKA-dependent signaling (3).MMP-13 is a collagenase that is expressed in chondrocytes, osteoblasts, and osteocytes. It plays an essential role in early stages of endochondral bone formation, and its expression is increased in pathological conditions such as osteoarthritis, rheumatoid arthritis, and tumor metastasis (4 -6). Mmp-13 gene expression is highly stimulated by PTH in osteoblastic UMR 106-01 cells (7), as well as in vivo (8). The relevance of MMP-13 and PTH has been demonstrated in vivo by the decreased expression of MMP-...

“…Runx2 Increases Snail Expression through p300-mediated Histone Acetylation-Runx2 has been reported to associate with histone acetyltransferase p300 and then to increase the expression of the cancer invasion-related gene (23). We used the TFSearch computational tool to search for p300 binding sites in Snail promoter.…”

Section: Runx2 Is Required For Bmp-2-induced Snail Up-regulation and mentioning

confidence: 99%

Lung Tumor-associated Osteoblast-derived Bone Morphogenetic Protein-2 Increased Epithelial-to-Mesenchymal Transition of Cancer by Runx2/Snail Signaling Pathway

Hsu

Huang

Yang

et al. 2011

Bone is a frequent target of lung cancer metastasis and is associated with significant morbidity and a dismal prognosis. Interaction between cancer cells and the bone microenvironment causes a vicious cycle of tumor progression and bone destruction. This study analyzed the soluble factors secreted by lung tumor-associated osteoblast (TAOB), which are responsible for increasing cancer progression. The addition of bone morphogenetic protein-2 (BMP-2), present in large amounts in TAOB conditioned medium (TAOB-CM) and lung cancer patient sera, mimicked the inductive effect of TAOB-CM on lung cancer migration, invasion, and epithelial-to-mesenchymal transition. In contrast, inhibition of BMP by noggin decreases the inductive properties of TAOB-CM and lung cancer patient sera on cancer progression. Induction of lung cancer migration by BMP-2 is associated with increased ERK and p38 activation and the upregulation of Runx2 and Snail. Blocking ERK and p38 by a specific inhibitor significantly decreases cancer cell migration by inhibiting Runx2 up-regulation and subsequently attenuating the expression of Snail. Enhancement of Runx2 facilitates Rux2 to recruit p300, which in turn enhances histone acetylation, increases Snail expression, and decreases E-cadherin. Furthermore, inhibiting Runx2 by siRNA also suppresses BMP-2-induced Snail up-regulation and cell migration. Our findings provide novel evidence that inhibition of BMP-2 or BMP-2-mediated MAPK/Runx2/Snail signaling is an attractive therapeutic target for osteolytic bone metastases in lung cancer patients.The skeleton is a frequent target of lung cancer metastasis. Approximately 30 -40% of patients with advanced lung cancer will develop bone metastasis, resulting in a dramatic increase of mortality rates and severely diminishing quality of life (1, 2). Bone metastasis are usually symptomatic, the most frequent pain complained by cancer patients is pain from bone metastases. Approximately 80% of lung cancer patients with bone metastases may suffer from localized bone pain, followed by extremity weakness (14.9%) (3, 4). Skeletal-related events, including pathologic fracture, spinal cord compression, hypercalcemia, or pain requiring surgery, radiotherapy, or opioid analgesics. Most lung cancer patients with bone metastases experience impaired quality of life because of pathologic bone fracture, especially the long bones, significantly impairing their functional status (4). The median survival time of lung cancer with synchronous bone metastasis ranges from 5 to 6 months, and the 2-year survival rate is only 3% (3). Interaction between cancer cells and the bone microenvironment causes a vicious cycle of tumor progression and bone destruction (5, 6). Cancer cells produce some soluble factors that alter osteoblast and osteoclast proliferation, maturation, and activation, resulting in an increase of bone resorption. In addition, resorption of the bone matrix causes the release of soluble factors that enhance cancer cell growth and promote metastasis from the primary site ...