Polyplexes based on polycarbonate polymers and siRNA against HDAC7 for a targeted anti-angiogenic therapy
Frère, Antoine ; Peixoto, Paul ; Mottet, Denis et al
Conference (2013, October 17)Detailed reference viewed: 10 (0 ULg)
The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2
Peulen, Olivier ; ; Peixoto, Paul et al
in PLoS ONE (2013), 8(9), 75102
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 ... [more ▼]
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC) model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients. [less ▲]Detailed reference viewed: 23 (11 ULg)
A new role for histone deacetylase 5 in the maintenance of long telomeres.
; Polese, Catherine ; Matheus, Nicolas et al
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2013), 27
Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin ... [more ▼]
Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin remodeling is probably the least studied; thus, we intended to explore the role of a specific histone deacetylase on telomere maintenance. We uncovered a new role for histone deacetylase 5 (HDAC5) in telomere biology. We report that HDAC5 is recruited to the long telomeres of osteosarcoma- and fibrosarcoma-derived cell lines, where it ensures proper maintenance of these repetitive regions. Indeed, depletion of HDAC5 by RNAi resulted in the shortening of longer telomeres and homogenization of telomere length in cells that use either telomerase or an alternative mechanism of telomere maintenance. Furthermore, we present evidence for the activation of telomere recombination on depletion of HDAC5 in fibrosarcoma telomerase-positive cancer cells. Of potential importance, we also found that depletion of HDAC5 sensitizes cancer cells with long telomeres to chemotherapeutic drugs. Cells with shorter telomeres were used to control the specificity of HDAC5 role in the maintenance of long telomeres. HDAC5 is essential for the length maintenance of long telomeres and its depletion is required for sensitization of cancer cells with long telomeres to chemotherapy. -Novo, C. L., Polese, C., Matheus, N., Decottignies, A., Londono-Vallejo, A., Castronovo, V., Mottet, D. A new role for histone deacetylase 5 in the maintenance of long telomeres. [less ▲]Detailed reference viewed: 69 (22 ULg)
Concomitant inhibition of class I HDAC and COX-2 exerts a antitumor effect in a human pancreatic cancer model
Gonzalez, Arnaud ; Peixoto, Paul ; Turtoi, Andrei et al
Poster (2013, July 11)
- Introduction : Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in developed countries. Early-stage pancreatic cancer is usually clinically silent, and disease only ... [more ▼]
- Introduction : Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in developed countries. Early-stage pancreatic cancer is usually clinically silent, and disease only becomes apparent after the tumor invades surrounding tissues or metastatises to distant organs. Moreover, the current chemotherapeutic treatments have no or few effects on this type of cancer, increasing only slightly the median survival of the patients. The survival rate at 5-years is only 3%. There is a need to develop new effective therapies for PDAC patients together with a robust and fast in vivo model allowing drug screening. In this study, We tested whether the combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC) may result in a better control of PDAC. We improved the formation of pancreatic tumor on Chorioallantoic membrane (CAM), an alternative to murine model. - Methods : The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed in vitro on human pancreas BxPC-3 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib) or HDAC1/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we improved, characterized and used model of pancreas tumors growing on chick chorioallantoic membrane. - Results : The inhibition of HDAC1/3 by SiRNA or MS-275 treatment reduced significantly the growth of BxPC-3 cells in vitro. Furthermore, we showed by QPCR and immunoblotting that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 at least via the NF-kB pathway. Based on this observation, we decided to test the effect of MS-275 combined with celecoxib a COX-2 inhibitor. This combination was more effective then either drug used alone to reduce the growth of BxPC-3 cells. By FACS analysis we showed that MS-275/celecoxib combination decreased significantly the proportion of cells in S phase and increased significantly and drastically the proportion in G0/G1 at 24, 48 and 72h. By immunobloting this GO/G1 arrest was confirmed by accumulation of cell cycle repressors (P21, P27) and disappearance of hyper phosphorylated form of RB protein. Following a procedure development, we produced on CAM 60 mm3 functionally vascularized tumors mimicking human pancreatic tumors on CAM model. The clinical relevance of this model is supported by the CK7+/CK19+/CK20-/CEA+/Ki67+/CD56- immunolabeling. Recently we have discovered several novel biomarkers of human PDAC: MYOF, TGFBI, LTBP2. These antigens were expressed in tumors grown on CAM, reaffirming its clinical relevance. The concept of the co-treatment by MS-275 and celecoxib was validated using this model. We showed that celecoxib alone did not significantly reduce tumor growth. MS-275 alone decreased tumor growth by 50% and combination of celecoxib and MS-275 stalled entirely the tumor growth. - Conclusions : Our data demonstrate a significant synergic anti-tumoral action of HDAC and COX-2 inhibitors, which set a basis for the development of potentially effective new combinatory therapies for PDAC patients. [less ▲]Detailed reference viewed: 11 (3 ULg)
PP2A regulatory subunit Balpha controls endothelial contractility and vessel lumen integrity via regulation of HDAC7.
Martin, Maud ; ; et al
in EMBO Journal (2013)
To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens ... [more ▼]
To supply tissues with nutrients and oxygen, the cardiovascular system forms a seamless, hierarchically branched, network of lumenized tubes. Here, we show that maintenance of patent vessel lumens requires the Balpha regulatory subunit of protein phosphatase 2A (PP2A). Deficiency of Balpha in zebrafish precludes vascular lumen stabilization resulting in perfusion defects. Similarly, inactivation of PP2A-Balpha in cultured ECs induces tubulogenesis failure due to alteration of cytoskeleton dynamics, actomyosin contractility and maturation of cell-extracellular matrix (ECM) contacts. Mechanistically, we show that PP2A-Balpha controls the activity of HDAC7, an essential transcriptional regulator of vascular stability. In the absence of PP2A-Balpha, transcriptional repression by HDAC7 is abrogated leading to enhanced expression of the cytoskeleton adaptor protein ArgBP2. ArgBP2 hyperactivates RhoA causing inadequate rearrangements of the EC actomyosin cytoskeleton. This study unravels the first specific role for a PP2A holoenzyme in development: the PP2A-Balpha/HDAC7/ArgBP2 axis maintains vascular lumens by balancing endothelial cytoskeletal dynamics and cell-matrix adhesion. [less ▲]Detailed reference viewed: 9 (3 ULg)
Characterization and transfection experiments of polyplexes targeting HDAC7
Frère, Antoine ; ; Collard, Laurence et al
Poster (2012, October 22)Detailed reference viewed: 18 (12 ULg)
The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells.
Castronovo, Vincenzo ; Matheus, Nicolas ; Dumont, Bruno et al
Conference (2012, April 21)Detailed reference viewed: 66 (26 ULg)
HDAC5 is required for maintenance of pericentric heterochromatin and controls cell cycle progression of human cancer cells
Peixoto, Paul ; Matheus, Nicolas ; Polese, Catherine et al
Poster (2012, February 04)Detailed reference viewed: 21 (6 ULg)
Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance.
; ; Mottet, Denis et al
in EMBO Journal (2012)
Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of ... [more ▼]
Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. [less ▲]Detailed reference viewed: 13 (0 ULg)
The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells.
Turtoi, Andrei ; Mottet, Denis ; Matheus, Nicolas et al
in Angiogenesis (2012)
Histone deacetylases (HDACs) are a family of 18 enzymes that deacetylate lysine residues of both histone and nonhistone proteins and to a large extent govern the process of angiogenesis. Previous studies ... [more ▼]
Histone deacetylases (HDACs) are a family of 18 enzymes that deacetylate lysine residues of both histone and nonhistone proteins and to a large extent govern the process of angiogenesis. Previous studies have shown that specific inhibition of HDAC7 blocks angiogenesis both in vitro and in vivo. However, the underlying molecular mechanisms are not fully understood and hence preclude any meaningful development of suitable therapeutic modalities. The goal of the present study was to further the understanding of HDAC7 epigenetic control of angiogenesis in human endothelial cells using the proteomic approach. The underlying problem was approached through siRNA-mediated gene-expression silencing of HDAC7 in human umbilical vein endothelial cells (HUVECs). To this end, HUVEC proteins were extracted and proteomically analyzed. The emphasis was placed on up-regulated proteins, as these may represent potential direct epigenetic targets of HDAC7. Among several proteins, A-kinase anchor protein 12 (AKAP12) was the most reproducibly up-regulated protein following HDAC7 depletion. This overexpression of AKAP12 was responsible for the inhibition of migration and tube formation in HDAC7-depleted HUVEC. Mechanistically, H3 histones associated with AKAP12 promoter were acetylated following the removal of HDAC7, leading to an increase in its mRNA and protein levels. AKAP12 is responsible for protein kinase C mediated phosphorylation of signal transducer and activator of transcription 3 (STAT3). Phosphorylated STAT3 increasingly binds to the chromatin and AKAP12 promoter and is necessary for maintaining the elevated levels of AKAP12 following HDAC7 knockdown. We demonstrated for the first time that AKAP12 tumor/angiogenesis suppressor gene is an epigenetic target of HDAC7, whose elevated levels lead to a negative regulation of HUVEC migration and inhibit formation of tube-like structures. [less ▲]Detailed reference viewed: 30 (9 ULg)
HDAC5 is required for maintenance of pericentric heterochromatin, and controls cell-cycle progression and survival of human cancer cells
Peixoto, Paul ; Castronovo, Vincenzo ; Matheus, Nicolas et al
in Cell Death & Differentiation (2012)
Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer ... [more ▼]
Histone deacetylases (HDACs) form a family of enzymes, which have fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. In this study, we further investigated the biological function of HDAC5 in cancer cells. We found HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. We demonstrated that specific depletion of HDAC5 by RNA interference resulted in profound changes in the heterochromatin structure and slowed down ongoing replication forks. This defect in heterochromatin maintenance and assembly are sensed by DNA damage checkpoint pathways, which triggered cancer cells to autophagy and apoptosis, and arrested their growth both in vitro and in vivo. Finally, we also demonstrated that HDAC5 depletion led to enhanced sensitivity of DNA to DNA-damaging agents, suggesting that heterochromatin de-condensation induced by histone HDAC5 silencing may enhance the efficacy of cytotoxic agents that act by targeting DNA in vitro. Together, these results highlighted for the first time an unrecognized link between HDAC5 and the maintenance/assembly of heterochromatin structure, and demonstrated that its specific inhibition might contribute to increase the efficacy of DNA alteration-based cancer therapies in clinic. [less ▲]Detailed reference viewed: 80 (48 ULg)
Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes.
; ; Mottet, Denis et al
in Journal of Immunology (2011), 186(8), 4782-93
CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent ... [more ▼]
CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jalpha segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. [less ▲]Detailed reference viewed: 16 (9 ULg)
Histone deacetylase 5 is a regulator of S phase progression
Peixoto, Paul ; Pirotte, Sophie ; Matheus, Nicolas et al
Poster (2011, February 05)Detailed reference viewed: 14 (5 ULg)
Dentin Matrix Protein 1 induces membrane expression of VE-cadherin on endothelial cells and inhibits VEGF-induced angiogenesis by blocking VEGFR-2 phosphorylation.
Pirotte, Sophie ; Lamour, Virginie ; Lambert, Vincent et al
in Blood (2011), 117(8), 2515-26
Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices ... [more ▼]
Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although pro-angiogenic activities have been demonstrated for two SIBLINGs, the role of DMP1 in angiogenesis has not been addressed yet. We demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate VEGFR-2 activity, the major high affinity receptor for VEGF. DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner. VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC. Indeed, subsequently to VE-cadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with bFGF-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis. [less ▲]Detailed reference viewed: 157 (41 ULg)
Histone deacetylases: anti-angiogenic targets in cancer therapy.
Mottet, Denis ; Castronovo, Vincenzo
in Current Cancer Drug Targets (2010), 10(8), 898-913
Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost ... [more ▼]
Judah Folkman was the first in 1971 to observe and report that cancer growth and dissemination were dependent on angiogenesis - the formation of new blood vessels from pre-existing vasculature. For almost 40 years, this concept has inspired generations of researchers to identify anti-angiogenic molecules that could be used therapeutically to stop blood vessels formation and starve tumors of nutrients and oxygen. Tumor angiogenesis requires complex cellular and molecular interactions between endothelial and cancer cells. In response to external stimuli such as hypoxia, cancer cells secrete pro-angiogenic factors into the extracellular matrix that activate the surrounding endothelial cells to proliferate, migrate and form new blood vessels. So, vascularization of malignant lesions depends on the expression of specific genes in both endothelial and tumor cells and accumulating evidences shows that several members of the histone deacetylase (HDAC) family play key roles in the regulation of these genes. Indeed, numerous in vitro and in vivo studies demonstrated that inhibitors of HDAC modulate angiogenic gene expression in both endothelial and cancer cells and disturb the delicate and complex balance between the collective action of pro-angiogenic factors and angiogenesis inhibitors. Thus, HDAC are currently recognized as promising targets for the development of anti-cancer drugs. This review is an effort to present and discuss the role, functions and mechanisms of action of HDAC during tumor-driven angiogenesis as well as a brief summary of the clinical status of the main HDAC inhibitors (HDACi) currently under development in cancer therapy. [less ▲]Detailed reference viewed: 64 (15 ULg)
HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.
Mottet, Denis ; Pirotte, Sophie ; Lamour, Virginie et al
in Oncogene (2009), 28(2), 243-56
Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II ... [more ▼]
Cancer cells have complex, unique characteristics that distinguish them from normal cells, such as increased growth rates and evasion of anti-proliferative signals. Global inhibition of class I and II histone deacetylases (HDACs) stops cancer cell proliferation in vitro and has proven effective against cancer in clinical trials, at least in part, through transcriptional reactivation of the p21(WAF1/Cip1)gene. The HDACs that regulate p21(WAF1/Cip1) are not fully identified. Using small interfering RNAs, we found that HDAC4 participates in the repression of p21(WAF1/Cip1) through Sp1/Sp3-, but not p53-binding sites. HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1). Induction of p21(WAF1/Cip1) mediated by silencing of HDAC4 arrested cancer cell growth in vitro and inhibited tumor growth in an in vivo human glioblastoma model. Thus, HDAC4 could be a useful target for new anti-cancer therapies based on selective inhibition of specific HDACs. [less ▲]Detailed reference viewed: 86 (22 ULg)
Les histones desacetylases : nouvelles cibles pour les therapies anti-cancereuses.
Mottet, Denis ; Castronovo, Vincenzo
in Medecine Sciences : M/S (2008), 24(8-9), 742-6
Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred ... [more ▼]
Circa twenty-five years ago, cancer research was dominated by the concept that the origin of cancer was genetic. Thousands of genetic alterations have indeed been identified involving more than hundred different genes in cancer development. Today, the model has evolved: it has been demonstrated that malignancies can be initiated not only through genetic alterations but also through epigenetic deregulations. By altering the expression of gene involved in cell regulation, epigenetic alterations, such as histone acetylation, play a key role in the initiation and progression of neoplasm. It has been shown that an imbalance between the acelylated and deacetylated status of chromatin is significantly involved in the acquisition of a malignant phenotype. Thus, the modulation of the histone acetylation level by histone deacetylase (HDAC) inhibitors could lead to a genetic re-programmation in cancer cells that would favor apoptosis and prevent proliferation. The potential therapeutic value of several HDAC inhibitors for cancer patients has been evaluated in clinical assays with very promising outcome. Indeed, the first inhibitors available for patients has been recently approved for cancer patients tracing the way for a new class of promising anti-cancer therapy modalities. [less ▲]Detailed reference viewed: 58 (6 ULg)
Histone deacetylase 7 silencing alters endothelial cell migration, a key step in angiogenesis
Mottet, Denis ; Bellahcene, Akeila ; Pirotte, Sophie et al
in Circulation Research (2007), 101(12), 1237-1246
Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the ... [more ▼]
Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-beta) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein kinase D activation pathway and induced, similarly to HDAC7 silencing, an increase in PDGF-B expression, as well as a partial inhibition of endothelial cell migration. Collectively, these data identified HDAC7 as a key modulator of endothelial cell migration and hence angiogenesis, at least in part, by regulating PDGF-B/PDGFR-beta gene expression. Because angiogenesis is required for tumor progression, HDAC7 may represent a rational target for therapeutic intervention against cancer. [less ▲]Detailed reference viewed: 47 (16 ULg)
Histone Deacetylases: Target Enzymes for Cancer Therapy
Mottet, Denis ; Castronovo, Vincenzo
in Clinical & Experimental Metastasis (2007)
Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups ... [more ▼]
Epigenic regulation of gene transcription has recently been the subject of a fast growing interest particularly in the field of cancer. Enzymatic acetylation and deacetylation of the epsilon-amino groups of lysine residues from nucleosomal histones, represents major molecular epigenic mechanisms controlling gene expression. Histone deacetylases (HDACs) and histone acetyl transferases (HAT) represent the two families of enzymes in charge of the control of the level of acetylation of the histone tails. By removing the acetyl groups that abrogate the positive charge of the lysine residues that maintain the histone tails attached to DNA, HDACs repress transcription. In mammals, these latter enzymes form three groups of related enzymes based on their sequence homology and are classified as HDACs I, II and III. Global inhibition of the HDACs I and II groups results in cell growth arrest and apoptosis of cancer cells and alters tumor growth in in vivo experimental models. Their surprisingly low general toxicity and their impressive efficiency in preclinical cancer models has led to consider HDAC inhibitors as very promising new anticancer pharmacological agents. In this review, we attempt to give a comprehensive overview of the role and the involvement of HDAC in carcinogenesis as well as the current progress on the development of HDAC general and specific inhibitors as new cancer therapies. [less ▲]Detailed reference viewed: 23 (5 ULg)
Role for casein kinase 2 in the regulation of HIF-1 activity.
Mottet, Denis ; ; et al
in International Journal of Cancer = Journal International du Cancer (2005), 117(5), 764-74
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in ... [more ▼]
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1alpha subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1alpha degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the beta subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the alpha subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2alpha, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxia-induced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1alpha protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. [less ▲]Detailed reference viewed: 18 (0 ULg)