The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
David W. Christianson - One of the best experts on this subject based on the ideXlab platform.
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X-ray Crystallographic Snapshots of Substrate Binding in the Active Site of Histone Deacetylase 10.
Biochemistry, 2021Co-Authors: Corey J Herbst-gervasoni, David W. ChristiansonAbstract:Histone Deacetylase 10 (HDAC10) is a zinc-dependent polyamine Deacetylase enriched in the cytosol of eukaryotic cells. The active site of HDAC10 contains catalytic residues conserved in other HDAC isozymes that function as lysine Deacetylases: Y307 assists the zinc ion in polarizing the substrate carbonyl for nucleophilic attack, and the H136-H137 dyad serves general base-general acid functions. As an inducer of autophagy, HDAC10 is an attractive target for the design of selective inhibitors that may be useful in cancer chemotherapy. Because detailed structural information regarding the catalytic mechanism of HDAC10 may inform new approaches to inhibitor design, we now report X-ray crystal structures of HDAC10 in which reaction intermediates with substrates N8-acetylspermidine and N-acetylputrescine are trapped in the active site. The Y307F substitution prevents activation of the substrate carbonyl for nucleophilic attack by the zinc-bound water molecule, thereby enabling crystallographic isolation of intact enzyme-substrate complexes. The H137A substitution removes the catalytically obligatory general acid, thereby enabling crystallographic isolation of oxyanionic tetrahedral intermediates. Finally, the acetate complex with the wild-type enzyme represents a product complex after dissociation of the polyamine coproduct. Taken together, these structures provide snapshots of the reaction coordinate of acetylpolyamine hydrolysis and are consistent with a mechanism in which tandem histidine residues H136 and H137 serve as general base and general acid catalysts, respectively. The function of the histidine dyad in the HDAC10 mechanism appears to be similar to that in HDAC6, but not HDAC8 in which both functions are served by the second histidine of the tandem pair.
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Binding of N8-Acetylspermidine Analogues to Histone Deacetylase 10 Reveals Molecular Strategies for Blocking Polyamine Deacetylation.
Biochemistry, 2019Co-Authors: Corey J Herbst-gervasoni, David W. ChristiansonAbstract:Eukaryotic Histone Deacetylase 10 (HDAC10) is a Zn2+-dependent hydrolase that exhibits catalytic specificity for the hydrolysis of the polyamine N8-acetylspermidine. The recently determined crystal structure of HDAC10 from Danio rerio (zebrafish) reveals a narrow active site cleft and a negatively charged "gatekeeper" (E274) that favors the binding of the slender cationic substrate. Because HDAC10 expression is upregulated in advanced-stage neuroblastoma and induces autophagy, the selective inhibition of HDAC10 suppresses the autophagic response and renders cancer cells more susceptible to cytotoxic chemotherapeutic drugs. Here, we describe X-ray crystal structures of zebrafish HDAC10 complexed with eight different analogues of N8-acetylspermidine. These analogues contain different Zn2+-binding groups, such as hydroxamate, thiolate, and the tetrahedral gem-diolate resulting from the addition of a Zn2+-bound water molecule to a ketone carbonyl group. Notably, the chemistry that accompanies the binding of ketonic substrate analogues is identical to the chemistry involved in the first step of catalysis, i.e., nucleophilic attack of a Zn2+-bound water molecule at the scissile carbonyl group of N8-acetylspermidine. The most potent inhibitor studied contains a thiolate Zn2+-binding group. These structures reveal interesting geometric changes in the metal coordination polyhedron that accommodate inhibitor binding. Additional interactions in the active site highlight features contributing to substrate specificity. These interactions are likely to contribute to inhibitor binding selectivity and will inform the future design of compounds selective for HDAC10 inhibition.
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Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth HalophileMarinobacter subterrani.
Biochemistry, 2019Co-Authors: Jeremy D. Osko, Stephen A. Shinsky, Benjamin W. Roose, David W. ChristiansonAbstract:Polyamines are small organic cations that are essential for cellular function in all kingdoms of life. Polyamine metabolism is regulated by enzyme-catalyzed acetylation-deacetylation cycles in a fashion similar to the epigenetic regulation of Histone function in eukaryotes. Bacterial polyamine Deacetylases are particularly intriguing, because these enzymes share the fold and function of eukaryotic Histone Deacetylases. Recently, acetylpolyamine amidohydrolase from the deep earth halophile Marinobacter subterrani (msAPAH) was described. This Zn2+-dependent Deacetylase shares 53% amino acid sequence identity with the acetylpolyamine amidohydrolase from Mycoplana ramosa (mrAPAH) and 22% amino acid sequence identity with the catalytic domain of Histone Deacetylase 10 from Danio rerio (zebrafish; zHDAC10), the eukaryotic polyamine Deacetylase. The X-ray crystal structure of msAPAH, determined in complexes with seven different inhibitors as well as the acetate coproduct, shows how the chemical strategy of Zn2+-dependent amide hydrolysis and the catalytic specificity for cationic polyamine substrates is conserved in a subterranean halophile. Structural comparisons with mrAPAH reveal that an array of aspartate and glutamate residues unique to msAPAH enable the binding of one or more Mg2+ ions in the active site and elsewhere on the protein surface. Notwithstanding these differences, activity assays with a panel of acetylpolyamine and acetyllysine substrates confirm that msAPAH is a broad-specificity polyamine Deacetylase, much like mrAPAH. The broad substrate specificity contrasts with the narrow substrate specificity of zHDAC10, which is highly specific for N8-acetylspermidine hydrolysis. Notably, quaternary structural features govern the substrate specificity of msAPAH and mrAPAH, whereas tertiary structural features govern the substrate specificity of zHDAC10.
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Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10.
Biochemistry, 2018Co-Authors: Stephen A. Shinsky, David W. ChristiansonAbstract:Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well-defined, only recently has the molecular basis of reversible polyamine acetylation been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: Histone Deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine Deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine Deacetylase. Similar to the greater family of HDACs, which mainly serve as lysine Deacetylases, both enzymes adopt the characteristic arginase-Deacetylase fold and employ a Zn2+-activated water molecule for catalysis. In contrast with HDACs, however, the active sites of HDAC10 and APAH are sterically constri...
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Histone Deacetylase 10 structure and molecular function as a polyamine Deacetylase
Nature Communications, 2017Co-Authors: Yang Hai, Stephen A. Shinsky, Nicholas J. Porter, David W. ChristiansonAbstract:Polyamines bind to nucleic acids and their function is regulated by reversible acetylation. Here, the authors show that Histone Deacetylase 10 is a polyamine Deacetylase and present its crystal structure with a bound polyamine transition state analogue inhibitor. Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that Histone Deacetylase 10 (HDAC10) is a robust polyamine Deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N ^8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.
Shichao Han - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 10 exerts anti-tumor effects on cervical cancer via a novel microRNA-223/TXNIP/Wnt/β-catenin pathway
IUBMB life, 2021Co-Authors: Jinming Zhu, Shichao HanAbstract:Dysfunction of Histone Deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened-out miRNA target. Microarray analysis and RT-qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR-233, upregulated in CC, was regulated by HDAC10 through Histone acetylation, while miR-233 inhibited the effects of HDAC10 overexpression in CC. miR-223 targeted the 3'-UTR of thioredoxin interacting protein (TXNIP) and suppressed its expression, leading to increased CC development in vitro and in vivo. TXNIP overexpression impaired Wnt/β-catenin pathway activity in CC cells. This article is protected by copyright. All rights reserved.
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Histone Deacetylase 10 exerts anti tumor effects on cervical cancer via a novel microrna 223 txnip wnt β catenin pathway
Iubmb Life, 2021Co-Authors: Jinming Zhu, Shichao HanAbstract:Dysfunction of Histone Deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened-out miRNA target. Microarray analysis and RT-qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR-233, upregulated in CC, was regulated by HDAC10 through Histone acetylation, while miR-233 inhibited the effects of HDAC10 overexpression in CC. miR-223 targeted the 3'-UTR of thioredoxin interacting protein (TXNIP) and suppressed its expression, leading to increased CC development in vitro and in vivo. TXNIP overexpression impaired Wnt/β-catenin pathway activity in CC cells. This article is protected by copyright. All rights reserved.
Jinming Zhu - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase 10 exerts anti-tumor effects on cervical cancer via a novel microRNA-223/TXNIP/Wnt/β-catenin pathway
IUBMB life, 2021Co-Authors: Jinming Zhu, Shichao HanAbstract:Dysfunction of Histone Deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened-out miRNA target. Microarray analysis and RT-qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR-233, upregulated in CC, was regulated by HDAC10 through Histone acetylation, while miR-233 inhibited the effects of HDAC10 overexpression in CC. miR-223 targeted the 3'-UTR of thioredoxin interacting protein (TXNIP) and suppressed its expression, leading to increased CC development in vitro and in vivo. TXNIP overexpression impaired Wnt/β-catenin pathway activity in CC cells. This article is protected by copyright. All rights reserved.
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Histone Deacetylase 10 exerts anti tumor effects on cervical cancer via a novel microrna 223 txnip wnt β catenin pathway
Iubmb Life, 2021Co-Authors: Jinming Zhu, Shichao HanAbstract:Dysfunction of Histone Deacetylase 10 (HDAC10) has been suggested in the carcinogenesis of cervical cancer (CC). However, its association with microRNAs (miRNAs) in CC remains exclusive. Hence, this study aims to probe the role of HDAC10 in regulating CC cell proliferation, migration, and invasion and its correlation with the screened-out miRNA target. Microarray analysis and RT-qPCR revealed that HDAC10 expressed poorly in CC cells relative to human immortalized endocervical cells (End1/E6E7). Moreover, HDAC10 downregulation predicted poor survival for patients with CC. Overexpression of HDAC10 reduced CC cell biological activities in vitro and tumor growth and lung metastases in vivo. miR-233, upregulated in CC, was regulated by HDAC10 through Histone acetylation, while miR-233 inhibited the effects of HDAC10 overexpression in CC. miR-223 targeted the 3'-UTR of thioredoxin interacting protein (TXNIP) and suppressed its expression, leading to increased CC development in vitro and in vivo. TXNIP overexpression impaired Wnt/β-catenin pathway activity in CC cells. This article is protected by copyright. All rights reserved.
Edward Seto - One of the best experts on this subject based on the ideXlab platform.
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HDAC10 Regulates Cancer Stem-like Cell Properties in KRAS-driven Lung Adenocarcinoma
Cancer research, 2020Co-Authors: Xiangyang Zhang, Shaoqi Zhu, Eden A. Dejene, Weiqun Peng, Antonia R Sepulveda, Edward SetoAbstract:Activation of oncogenic KRAS is the most common driving event in lung adenocarcinoma development. Despite the existing rationale for targeting activated KRAS and its downstream effectors, the failure of clinical trials to date indicates that the mechanism of KRAS-driven malignancy remains poorly understood. Here we report that Histone Deacetylase 10 (HDAC10) might function as a putative tumor suppressor in mice carrying a spontaneously activated oncogenic Kras allele. Hdac10 deletion accelerated KRAS-driven early-onset lung adenocarcinomas, increased macrophage infiltration in the tumor microenvironment, and shortened survival time in mice. Highly tumorigenic and stem-like lung adenocarcinoma cells were increased in Hdac10-deleted tumors compared with Hdac10 wild-type tumors. HDAC10 regulated the stem-like properties of KRAS-expressing tumor cells by targeting SOX9. Expression of SOX9 was significantly increased in Hdac10-deleted tumor cells and depletion of SOX9 in Hdac10 knockout (KO) lung adenocarcinoma cells inhibited growth of tumorspheres. The genes associated with TGFβ pathway were enriched in Hdac10 KO tumor cells, and activation of TGFβ signaling contributed to SOX9 induction in Hdac10 KO lung adenocarcinoma cells. Overall, our study evaluates the functions and mechanisms of action of HDAC10 in lung carcinogenesis that will inform the rationale for targeting its related regulatory signaling as an anticancer strategy. SIGNIFICANCE: These findings linking HDAC10 and lung tumorigenesis identify potential novel strategies for targeting HDAC10 as a treatment for lung cancer.
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Histone Deacetylase 10 regulates the cell cycle g2 m phase transition via a novel let 7 hmga2 cyclin a2 pathway
Molecular and Cellular Biology, 2015Co-Authors: Yixuan Li, Lirong Peng, Edward SetoAbstract:Histone Deacetylase (HDAC) inhibition leads to cell cycle arrest in G1 and G2, suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating Histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G2/M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating Histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation.
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Histone Deacetylase 10 Regulates the Cell Cycle G2/M Phase Transition via a Novel Let-7-HMGA2-Cyclin A2 Pathway.
Molecular and cellular biology, 2015Co-Authors: Lirong Peng, Edward SetoAbstract:Histone Deacetylase (HDAC) inhibition leads to cell cycle arrest in G1 and G2, suggesting HDACs as therapeutic targets for cancer and diseases linked to abnormal cell growth and proliferation. Many HDACs are transcriptional repressors. Some may alter cell cycle progression by deacetylating Histones and repressing transcription of key cell cycle regulatory genes. Here, we report that HDAC10 regulates the cell cycle via modulation of cyclin A2 expression, and cyclin A2 overexpression rescues HDAC10 knockdown-induced G2/M transition arrest. HDAC10 regulates cyclin A2 expression by deacetylating Histones near the let-7 promoter, thereby repressing transcription. In HDAC10 knockdown cells, let-7f and microRNA 98 (miR-98) were upregulated and the let-7 family target, HMGA2, was downregulated. HMGA2 loss resulted in enrichment of the transcriptional repressor E4F at the cyclin A2 promoter. These findings support a role for HDACs in cell cycle regulation, reveal a novel mechanism of HDAC10 action, and extend the potential of HDACs as targets in diseases of cell cycle dysregulation.
Stephen A. Shinsky - One of the best experts on this subject based on the ideXlab platform.
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Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth HalophileMarinobacter subterrani.
Biochemistry, 2019Co-Authors: Jeremy D. Osko, Stephen A. Shinsky, Benjamin W. Roose, David W. ChristiansonAbstract:Polyamines are small organic cations that are essential for cellular function in all kingdoms of life. Polyamine metabolism is regulated by enzyme-catalyzed acetylation-deacetylation cycles in a fashion similar to the epigenetic regulation of Histone function in eukaryotes. Bacterial polyamine Deacetylases are particularly intriguing, because these enzymes share the fold and function of eukaryotic Histone Deacetylases. Recently, acetylpolyamine amidohydrolase from the deep earth halophile Marinobacter subterrani (msAPAH) was described. This Zn2+-dependent Deacetylase shares 53% amino acid sequence identity with the acetylpolyamine amidohydrolase from Mycoplana ramosa (mrAPAH) and 22% amino acid sequence identity with the catalytic domain of Histone Deacetylase 10 from Danio rerio (zebrafish; zHDAC10), the eukaryotic polyamine Deacetylase. The X-ray crystal structure of msAPAH, determined in complexes with seven different inhibitors as well as the acetate coproduct, shows how the chemical strategy of Zn2+-dependent amide hydrolysis and the catalytic specificity for cationic polyamine substrates is conserved in a subterranean halophile. Structural comparisons with mrAPAH reveal that an array of aspartate and glutamate residues unique to msAPAH enable the binding of one or more Mg2+ ions in the active site and elsewhere on the protein surface. Notwithstanding these differences, activity assays with a panel of acetylpolyamine and acetyllysine substrates confirm that msAPAH is a broad-specificity polyamine Deacetylase, much like mrAPAH. The broad substrate specificity contrasts with the narrow substrate specificity of zHDAC10, which is highly specific for N8-acetylspermidine hydrolysis. Notably, quaternary structural features govern the substrate specificity of msAPAH and mrAPAH, whereas tertiary structural features govern the substrate specificity of zHDAC10.
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Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10.
Biochemistry, 2018Co-Authors: Stephen A. Shinsky, David W. ChristiansonAbstract:Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well-defined, only recently has the molecular basis of reversible polyamine acetylation been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: Histone Deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine Deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine Deacetylase. Similar to the greater family of HDACs, which mainly serve as lysine Deacetylases, both enzymes adopt the characteristic arginase-Deacetylase fold and employ a Zn2+-activated water molecule for catalysis. In contrast with HDACs, however, the active sites of HDAC10 and APAH are sterically constri...
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Histone Deacetylase 10 structure and molecular function as a polyamine Deacetylase
Nature Communications, 2017Co-Authors: Yang Hai, Stephen A. Shinsky, Nicholas J. Porter, David W. ChristiansonAbstract:Polyamines bind to nucleic acids and their function is regulated by reversible acetylation. Here, the authors show that Histone Deacetylase 10 is a polyamine Deacetylase and present its crystal structure with a bound polyamine transition state analogue inhibitor. Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that Histone Deacetylase 10 (HDAC10) is a robust polyamine Deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 Å-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N ^8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.
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Histone Deacetylase 10 structure and molecular function as a polyamine Deacetylase.
Nature communications, 2017Co-Authors: Yang Hai, Stephen A. Shinsky, Nicholas J. Porter, David W. ChristiansonAbstract:Cationic polyamines such as spermidine and spermine are critical in all forms of life, as they regulate the function of biological macromolecules. Intracellular polyamine metabolism is regulated by reversible acetylation and dysregulated polyamine metabolism is associated with neoplastic diseases such as colon cancer, prostate cancer and neuroblastoma. Here we report that Histone Deacetylase 10 (HDAC10) is a robust polyamine Deacetylase, using recombinant enzymes from Homo sapiens (human) and Danio rerio (zebrafish). The 2.85 A-resolution crystal structure of zebrafish HDAC10 complexed with a transition-state analogue inhibitor reveals that a glutamate gatekeeper and a sterically constricted active site confer specificity for N8-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Both HDAC10 and spermidine are known to promote cellular survival through autophagy. Accordingly, this work sets a foundation for studying the chemical biology of autophagy through the structure-based design of inhibitors that may also serve as new leads for cancer chemotherapy.