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Makoto Tsuneoka - One of the best experts on this subject based on the ideXlab platform.

  • Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription.
    Cells, 2020
    Co-Authors: Yuji Tanaka, Hideru Obinata, Akimitsu Konishi, Noriyuki Yamagiwa, Makoto Tsuneoka
    Abstract:

    Metformin, which is suggested to have anti-cancer effects, activates KDM2A to reduce rRNA transcription and proliferation of cancer cells. Thus, the specific activation of KDM2A may be applicable to the treatment of cancers. In this study, we screened a food-additive compound library to identify compounds that control cell proliferation. We found that gallic acid activated KDM2A to reduce rRNA transcription and cell proliferation in breast cancer MCF-7 cells. Gallic acid accelerated ROS production and activated AMPK. When ROS production or AMPK activity was inhibited, gallic acid did not activate KDM2A. These results suggest that both ROS production and AMPK activation are required for activation of KDM2A by gallic acid. Gallic acid did not reduce the succinate level, which was required for KDM2A activation by metformin. Metformin did not elevate ROS production. These results suggest that the activation of KDM2A by gallic acid includes mechanisms distinct from those by metformin. Therefore, signals from multiple intracellular conditions converge in KDM2A to control rRNA transcription. Gallic acid did not induce KDM2A-dependent anti-proliferation activity in non-tumorigenic MCF10A cells. These results suggest that the mechanism of KDM2A activation by gallic acid may be applicable to the treatment of breast cancers.

  • Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level
    Scientific reports, 2019
    Co-Authors: Yuji Tanaka, Hideru Obinata, Akimitsu Konishi, Makoto Tsuneoka
    Abstract:

    Metformin is used to treat type 2 diabetes. Metformin activates AMP-activated kinase (AMPK), which may contribute to the action of metformin. Metformin also shows anti-proliferation activity. However, the mechanism is remained unknown. We found that treatment of MCF-7 cells with metformin induced the demethylase activity of KDM2A in the rDNA promoter, which resulted in reductions of rRNA transcription and cell proliferation. AMPK activity was required for activation of KDM2A by metformin. Because demethylase activities of JmjC-type enzymes require a side reaction converting α-ketoglutarate to succinate, these organic acids may affect their demethylase activities. We found that metformin did not induce KDM2A demethylase activity in conditions of a reduced level of α-ketoglutarate. A four-hour treatment of metformin specifically reduced succinate, and the replenishment of succinate inhibited the activation of KDM2A by metformin, but did not inhibit the activation of AMPK. Metformin reduced succinate even in the conditions suppressing AMPK activity. These results indicate that metformin activates AMPK and reduces the intracellular succinate level, both of which are required for the activation of KDM2A to reduce rRNA transcription. The results presented here uncover a novel factor of metformin actions, reduction of the intracellular succinate, which contributes to the anti-proliferation activity of metformin.

  • KDM2A-dependent reduction of rRNA transcription on glucose starvation requires HP1 in cells, including triple-negative breast cancer cells.
    Oncotarget, 2019
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Chikashi Obuse, Sachiko Ogasawara, Jun-ichi Nakayama, Hirohisa Yano, Makoto Tsuneoka
    Abstract:

    Triple-negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets. Ribosome RNAs (rRNAs) are central components of ribosomes and transcribed in nucleoli, and the level of rRNA transcription greatly affects ribosome production and cell proliferation. We have reported that an epigenetic protein, KDM2A, exists in nucleoli and reduces rRNA transcription on glucose starvation. However, the molecular mechanism is still unclear. The purpose of this study is to examine the KDM2A-dependent regulation mechanism of rRNA transcription. In this study, we turned our attention to the nucleolar accumulation of KDM2A. We found that KDM2A had multiple regions for its nucleolar localization, and one of the regions was directly bound by heterochromatin protein 1γ (HP1γ) using valine 801 in the LxVxL motif of KDM2A. A knockdown of HP1γ or a point mutation of valine 801 in KDM2A decreased the nucleolar accumulation of KDM2A, and suppressed the reduction of rRNA transcription on glucose starvation. These results uncovered a novel function of HP1γ: the regulation of rRNA transcription, and suggested that HP1γ stimulates the nucleolar accumulation of KDM2A to support the KDM2A-dependent regulation of rRNA transcription. HP1γ was expressed in cancer cells in all breast carcinoma tissues examined, including TNBC tissues. A knockdown of HP1γ in a TNBC cell line, MDA-MB-231 cells, reduced the nucleolar accumulation of KDM2A, and suppressed the reductions of rRNA transcription and cell proliferation on glucose starvation. These results suggest that the KDM2A-dependent regulation of rRNA transcription requires HP1γ, and thus may be applicable to the treatment of TNBC.

  • SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells
    International journal of oncology, 2017
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Makoto Tsuneoka
    Abstract:

    Regulation of rRNA transcription is an important factor for control of cell proliferation. We previously found that the JmjC domain-containing demethylase KDM2A reduces H3K36me2 in the rRNA gene promoter and rRNA transcription under starvation, which results in suppression of cell proliferation. The KDM2A gene also produces another protein product, SF-KDM2A, which lacks a JmjC domain and has no demethylase activity. As yet, the function of SF-KDM2A is not clear. Recently, it was reported that KDM2A was frequently amplified and that elevated expression of KDM2A was significantly associated with short survival of breast cancer patients. SF-KDM2A was more abundant than full-length KDM2A in a subset of breast cancers. In the present study, we report that SF-KDM2A localized in nucleoli and bound to the rRNA gene promoter in breast cancer cells. Overexpression of SF-KDM2A stimulated the transcription of rRNA. While the zf-CXXC domain was required for SF-KDM2A binding to the rRNA gene promoter, SF-KDM2A with mutations in the zf-CXXC domain lost the binding to the rRNA gene promoter and did not stimulate rRNA transcription. Knockdown of SF-KDM2A reduced rRNA transcription and cell proliferation. When SF-KDM2A was overexpressed, a transcriptionally repressive mark, H4K20me3, in the rRNA gene promoter was specifically reduced in a zf-CXXC domain-dependent manner, and knockdown of SF-KDM2A increased the H4K20me3 level. Taken together, these results demonstrate that SF-KDM2A binds to the rRNA gene promoter, reduces the H4K20me3 level, and activates rRNA transcription, suggesting that the stimulation of rRNA transcription by SF-KDM2A may contribute to tumorigenesis in breast cancer.

  • Mild Glucose Starvation Induces KDM2A-Mediated H3K36me2 Demethylation through AMPK To Reduce rRNA Transcription and Cell Proliferation
    Molecular and cellular biology, 2015
    Co-Authors: Yuji Tanaka, Kengo Okamoto, Sachiko Ogasawara, Hirohisa Yano, Sho-ichi Yoshioka, Hiromi Imamura, Makoto Tsuneoka
    Abstract:

    Environmental conditions control rRNA transcription. Previously, we found that serum and glucose deprivation induces KDM2A-mediated H3K36me2 demethylation in the rRNA gene (rDNA) promoter and reduces rRNA transcription in the human breast cancer cell line MCF-7. However, the molecular mechanism and biological significance are still unclear. In the present study, we found that glucose starvation alone induced the KDM2A-dependent reduction of rRNA transcription. The treatment of cells with 2-deoxy-d-glucose, an inhibitor of glycolysis, reduced rRNA transcription and H3K36me2 in the rDNA promoter, both of which were completely dependent on KDM2A in low concentrations of 2-deoxy-d-glucose, that is, mild starvation conditions. The mild starvation induced these KDM2A activities through AMP-activated kinase (AMPK) but did not affect another AMPK effector of rRNA transcription, TIF-IA. In the triple-negative breast cancer cell line MDA-MB-231, the mild starvation also reduced rRNA transcription in a KDM2A-dependent manner. We detected KDM2A in breast cancer tissues irrespective of their estrogen receptor, progesterone receptor, and HER2 status, including triple-negative cancer tissues. In both MCF-7 and MDA-MB-231 cells, mild starvation reduced cell proliferation, and KDM2A knockdown suppressed the reduction of cell proliferation. These results suggest that under mild glucose starvation AMPK induces KDM2A-dependent reduction of rRNA transcription to control cell proliferation.

Yuji Tanaka - One of the best experts on this subject based on the ideXlab platform.

  • Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription.
    Cells, 2020
    Co-Authors: Yuji Tanaka, Hideru Obinata, Akimitsu Konishi, Noriyuki Yamagiwa, Makoto Tsuneoka
    Abstract:

    Metformin, which is suggested to have anti-cancer effects, activates KDM2A to reduce rRNA transcription and proliferation of cancer cells. Thus, the specific activation of KDM2A may be applicable to the treatment of cancers. In this study, we screened a food-additive compound library to identify compounds that control cell proliferation. We found that gallic acid activated KDM2A to reduce rRNA transcription and cell proliferation in breast cancer MCF-7 cells. Gallic acid accelerated ROS production and activated AMPK. When ROS production or AMPK activity was inhibited, gallic acid did not activate KDM2A. These results suggest that both ROS production and AMPK activation are required for activation of KDM2A by gallic acid. Gallic acid did not reduce the succinate level, which was required for KDM2A activation by metformin. Metformin did not elevate ROS production. These results suggest that the activation of KDM2A by gallic acid includes mechanisms distinct from those by metformin. Therefore, signals from multiple intracellular conditions converge in KDM2A to control rRNA transcription. Gallic acid did not induce KDM2A-dependent anti-proliferation activity in non-tumorigenic MCF10A cells. These results suggest that the mechanism of KDM2A activation by gallic acid may be applicable to the treatment of breast cancers.

  • Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level
    Scientific reports, 2019
    Co-Authors: Yuji Tanaka, Hideru Obinata, Akimitsu Konishi, Makoto Tsuneoka
    Abstract:

    Metformin is used to treat type 2 diabetes. Metformin activates AMP-activated kinase (AMPK), which may contribute to the action of metformin. Metformin also shows anti-proliferation activity. However, the mechanism is remained unknown. We found that treatment of MCF-7 cells with metformin induced the demethylase activity of KDM2A in the rDNA promoter, which resulted in reductions of rRNA transcription and cell proliferation. AMPK activity was required for activation of KDM2A by metformin. Because demethylase activities of JmjC-type enzymes require a side reaction converting α-ketoglutarate to succinate, these organic acids may affect their demethylase activities. We found that metformin did not induce KDM2A demethylase activity in conditions of a reduced level of α-ketoglutarate. A four-hour treatment of metformin specifically reduced succinate, and the replenishment of succinate inhibited the activation of KDM2A by metformin, but did not inhibit the activation of AMPK. Metformin reduced succinate even in the conditions suppressing AMPK activity. These results indicate that metformin activates AMPK and reduces the intracellular succinate level, both of which are required for the activation of KDM2A to reduce rRNA transcription. The results presented here uncover a novel factor of metformin actions, reduction of the intracellular succinate, which contributes to the anti-proliferation activity of metformin.

  • KDM2A-dependent reduction of rRNA transcription on glucose starvation requires HP1 in cells, including triple-negative breast cancer cells.
    Oncotarget, 2019
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Chikashi Obuse, Sachiko Ogasawara, Jun-ichi Nakayama, Hirohisa Yano, Makoto Tsuneoka
    Abstract:

    Triple-negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets. Ribosome RNAs (rRNAs) are central components of ribosomes and transcribed in nucleoli, and the level of rRNA transcription greatly affects ribosome production and cell proliferation. We have reported that an epigenetic protein, KDM2A, exists in nucleoli and reduces rRNA transcription on glucose starvation. However, the molecular mechanism is still unclear. The purpose of this study is to examine the KDM2A-dependent regulation mechanism of rRNA transcription. In this study, we turned our attention to the nucleolar accumulation of KDM2A. We found that KDM2A had multiple regions for its nucleolar localization, and one of the regions was directly bound by heterochromatin protein 1γ (HP1γ) using valine 801 in the LxVxL motif of KDM2A. A knockdown of HP1γ or a point mutation of valine 801 in KDM2A decreased the nucleolar accumulation of KDM2A, and suppressed the reduction of rRNA transcription on glucose starvation. These results uncovered a novel function of HP1γ: the regulation of rRNA transcription, and suggested that HP1γ stimulates the nucleolar accumulation of KDM2A to support the KDM2A-dependent regulation of rRNA transcription. HP1γ was expressed in cancer cells in all breast carcinoma tissues examined, including TNBC tissues. A knockdown of HP1γ in a TNBC cell line, MDA-MB-231 cells, reduced the nucleolar accumulation of KDM2A, and suppressed the reductions of rRNA transcription and cell proliferation on glucose starvation. These results suggest that the KDM2A-dependent regulation of rRNA transcription requires HP1γ, and thus may be applicable to the treatment of TNBC.

  • SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells
    International journal of oncology, 2017
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Makoto Tsuneoka
    Abstract:

    Regulation of rRNA transcription is an important factor for control of cell proliferation. We previously found that the JmjC domain-containing demethylase KDM2A reduces H3K36me2 in the rRNA gene promoter and rRNA transcription under starvation, which results in suppression of cell proliferation. The KDM2A gene also produces another protein product, SF-KDM2A, which lacks a JmjC domain and has no demethylase activity. As yet, the function of SF-KDM2A is not clear. Recently, it was reported that KDM2A was frequently amplified and that elevated expression of KDM2A was significantly associated with short survival of breast cancer patients. SF-KDM2A was more abundant than full-length KDM2A in a subset of breast cancers. In the present study, we report that SF-KDM2A localized in nucleoli and bound to the rRNA gene promoter in breast cancer cells. Overexpression of SF-KDM2A stimulated the transcription of rRNA. While the zf-CXXC domain was required for SF-KDM2A binding to the rRNA gene promoter, SF-KDM2A with mutations in the zf-CXXC domain lost the binding to the rRNA gene promoter and did not stimulate rRNA transcription. Knockdown of SF-KDM2A reduced rRNA transcription and cell proliferation. When SF-KDM2A was overexpressed, a transcriptionally repressive mark, H4K20me3, in the rRNA gene promoter was specifically reduced in a zf-CXXC domain-dependent manner, and knockdown of SF-KDM2A increased the H4K20me3 level. Taken together, these results demonstrate that SF-KDM2A binds to the rRNA gene promoter, reduces the H4K20me3 level, and activates rRNA transcription, suggesting that the stimulation of rRNA transcription by SF-KDM2A may contribute to tumorigenesis in breast cancer.

  • Mild Glucose Starvation Induces KDM2A-Mediated H3K36me2 Demethylation through AMPK To Reduce rRNA Transcription and Cell Proliferation
    Molecular and cellular biology, 2015
    Co-Authors: Yuji Tanaka, Kengo Okamoto, Sachiko Ogasawara, Hirohisa Yano, Sho-ichi Yoshioka, Hiromi Imamura, Makoto Tsuneoka
    Abstract:

    Environmental conditions control rRNA transcription. Previously, we found that serum and glucose deprivation induces KDM2A-mediated H3K36me2 demethylation in the rRNA gene (rDNA) promoter and reduces rRNA transcription in the human breast cancer cell line MCF-7. However, the molecular mechanism and biological significance are still unclear. In the present study, we found that glucose starvation alone induced the KDM2A-dependent reduction of rRNA transcription. The treatment of cells with 2-deoxy-d-glucose, an inhibitor of glycolysis, reduced rRNA transcription and H3K36me2 in the rDNA promoter, both of which were completely dependent on KDM2A in low concentrations of 2-deoxy-d-glucose, that is, mild starvation conditions. The mild starvation induced these KDM2A activities through AMP-activated kinase (AMPK) but did not affect another AMPK effector of rRNA transcription, TIF-IA. In the triple-negative breast cancer cell line MDA-MB-231, the mild starvation also reduced rRNA transcription in a KDM2A-dependent manner. We detected KDM2A in breast cancer tissues irrespective of their estrogen receptor, progesterone receptor, and HER2 status, including triple-negative cancer tissues. In both MCF-7 and MDA-MB-231 cells, mild starvation reduced cell proliferation, and KDM2A knockdown suppressed the reduction of cell proliferation. These results suggest that under mild glucose starvation AMPK induces KDM2A-dependent reduction of rRNA transcription to control cell proliferation.

Kengo Okamoto - One of the best experts on this subject based on the ideXlab platform.

  • KDM2A-dependent reduction of rRNA transcription on glucose starvation requires HP1 in cells, including triple-negative breast cancer cells.
    Oncotarget, 2019
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Chikashi Obuse, Sachiko Ogasawara, Jun-ichi Nakayama, Hirohisa Yano, Makoto Tsuneoka
    Abstract:

    Triple-negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets. Ribosome RNAs (rRNAs) are central components of ribosomes and transcribed in nucleoli, and the level of rRNA transcription greatly affects ribosome production and cell proliferation. We have reported that an epigenetic protein, KDM2A, exists in nucleoli and reduces rRNA transcription on glucose starvation. However, the molecular mechanism is still unclear. The purpose of this study is to examine the KDM2A-dependent regulation mechanism of rRNA transcription. In this study, we turned our attention to the nucleolar accumulation of KDM2A. We found that KDM2A had multiple regions for its nucleolar localization, and one of the regions was directly bound by heterochromatin protein 1γ (HP1γ) using valine 801 in the LxVxL motif of KDM2A. A knockdown of HP1γ or a point mutation of valine 801 in KDM2A decreased the nucleolar accumulation of KDM2A, and suppressed the reduction of rRNA transcription on glucose starvation. These results uncovered a novel function of HP1γ: the regulation of rRNA transcription, and suggested that HP1γ stimulates the nucleolar accumulation of KDM2A to support the KDM2A-dependent regulation of rRNA transcription. HP1γ was expressed in cancer cells in all breast carcinoma tissues examined, including TNBC tissues. A knockdown of HP1γ in a TNBC cell line, MDA-MB-231 cells, reduced the nucleolar accumulation of KDM2A, and suppressed the reductions of rRNA transcription and cell proliferation on glucose starvation. These results suggest that the KDM2A-dependent regulation of rRNA transcription requires HP1γ, and thus may be applicable to the treatment of TNBC.

  • SF-KDM2A binds to ribosomal RNA gene promoter, reduces H4K20me3 level, and elevates ribosomal RNA transcription in breast cancer cells
    International journal of oncology, 2017
    Co-Authors: Kengo Okamoto, Yuji Tanaka, Makoto Tsuneoka
    Abstract:

    Regulation of rRNA transcription is an important factor for control of cell proliferation. We previously found that the JmjC domain-containing demethylase KDM2A reduces H3K36me2 in the rRNA gene promoter and rRNA transcription under starvation, which results in suppression of cell proliferation. The KDM2A gene also produces another protein product, SF-KDM2A, which lacks a JmjC domain and has no demethylase activity. As yet, the function of SF-KDM2A is not clear. Recently, it was reported that KDM2A was frequently amplified and that elevated expression of KDM2A was significantly associated with short survival of breast cancer patients. SF-KDM2A was more abundant than full-length KDM2A in a subset of breast cancers. In the present study, we report that SF-KDM2A localized in nucleoli and bound to the rRNA gene promoter in breast cancer cells. Overexpression of SF-KDM2A stimulated the transcription of rRNA. While the zf-CXXC domain was required for SF-KDM2A binding to the rRNA gene promoter, SF-KDM2A with mutations in the zf-CXXC domain lost the binding to the rRNA gene promoter and did not stimulate rRNA transcription. Knockdown of SF-KDM2A reduced rRNA transcription and cell proliferation. When SF-KDM2A was overexpressed, a transcriptionally repressive mark, H4K20me3, in the rRNA gene promoter was specifically reduced in a zf-CXXC domain-dependent manner, and knockdown of SF-KDM2A increased the H4K20me3 level. Taken together, these results demonstrate that SF-KDM2A binds to the rRNA gene promoter, reduces the H4K20me3 level, and activates rRNA transcription, suggesting that the stimulation of rRNA transcription by SF-KDM2A may contribute to tumorigenesis in breast cancer.

  • Mild Glucose Starvation Induces KDM2A-Mediated H3K36me2 Demethylation through AMPK To Reduce rRNA Transcription and Cell Proliferation
    Molecular and cellular biology, 2015
    Co-Authors: Yuji Tanaka, Kengo Okamoto, Sachiko Ogasawara, Hirohisa Yano, Sho-ichi Yoshioka, Hiromi Imamura, Makoto Tsuneoka
    Abstract:

    Environmental conditions control rRNA transcription. Previously, we found that serum and glucose deprivation induces KDM2A-mediated H3K36me2 demethylation in the rRNA gene (rDNA) promoter and reduces rRNA transcription in the human breast cancer cell line MCF-7. However, the molecular mechanism and biological significance are still unclear. In the present study, we found that glucose starvation alone induced the KDM2A-dependent reduction of rRNA transcription. The treatment of cells with 2-deoxy-d-glucose, an inhibitor of glycolysis, reduced rRNA transcription and H3K36me2 in the rDNA promoter, both of which were completely dependent on KDM2A in low concentrations of 2-deoxy-d-glucose, that is, mild starvation conditions. The mild starvation induced these KDM2A activities through AMP-activated kinase (AMPK) but did not affect another AMPK effector of rRNA transcription, TIF-IA. In the triple-negative breast cancer cell line MDA-MB-231, the mild starvation also reduced rRNA transcription in a KDM2A-dependent manner. We detected KDM2A in breast cancer tissues irrespective of their estrogen receptor, progesterone receptor, and HER2 status, including triple-negative cancer tissues. In both MCF-7 and MDA-MB-231 cells, mild starvation reduced cell proliferation, and KDM2A knockdown suppressed the reduction of cell proliferation. These results suggest that under mild glucose starvation AMPK induces KDM2A-dependent reduction of rRNA transcription to control cell proliferation.

  • A CxxC domain that binds to unmethylated CpG is required for KDM2A to control rDNA transcription
    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 2015
    Co-Authors: Makoto Tsuneoka, Yuji Tanaka, Kengo Okamoto
    Abstract:

    Abstract   Dysfunction of ribosome biogenesis is commonly found in cancers. Because the transcription of ribosomal RNA genes (rDNA) is a rate-limiting step in ribosome biogenesis and is elevated in many cancer cells, ribosomal RNA transcription can be a target for cancer therapy. In eukaryotes, ribosomal RNA is transcribed specifically in nucleoli by RNA polymerase I but not by RNA polymerase II. Therefore, ribosomal RNA transcription by RNA polymerase I would have a distinct nature compared to transcription by RNA polymerase II. Genomic DNA with proteins including histones constitutes chromatin. The structure of chromatin has plasticity and is regulated by chemical modifications of chromatin's components. We had reported that histone demethylase KDM2A reduced ribosomal RNA transcription in response to starvation. In this symposium, we reported our recent results showing the mechanism by which KDM2A was recruited to rDNA chromatin. We found that KDM2A bound to a rDNA promoter with unmethylated CpG dinucleotides via KDM2A CxxC-zinc finger motif. This binding was required for KDM2A to demethylate histone in the rDNA promoter and reduce rDNA transcription resulting from starvation. Further, this binding was detected before starvation, independent of the demethylase activity. We also found that the histone demethylation by KDM2A in response to starvation was detected only in the rDNA promoter, but not in a gene promoter transcribed by Pol II, the P2RX4 promoter. These results suggest that it is important to consider genome regions and cell conditions when developing epigenetic drugs.

  • CxxC-ZF Domain Is Needed for KDM2A to Demethylate Histone in rDNA Promoter in Response to Starvation
    Cell structure and function, 2014
    Co-Authors: Yuji Tanaka, Kengo Okamoto, Toshiyuki Umata, Chikashi Obuse, Makoto Tsuneoka
    Abstract:

    The transcription of ribosomal RNA genes (rDNA) is a rate-limiting step in ribosome biogenesis and changes profoundly in response to environmental conditions. Recently we reported that JmjC demethylase KDM2A reduces rDNA transcription on starvation, with accompanying demethylation of dimethylated Lys 36 of histone H3 (H3K36me2) in rDNA promoter. Here, we characterized the functions of two domains of KDM2A, JmjC and CxxC-ZF domains. After knockdown of endogenous KDM2A, KDM2A was exogenously expressed. The exogenous wild-type KDM2A demethylated H3K36me2 in the rDNA promoter on starvation and reduced rDNA transcription as endogenous KDM2A. The exogenous KDM2A with a mutation in the JmjC domain lost the demethylase activity and did not reduce rDNA transcription on starvation, showing that the demethylase activity of KDM2A itself is required for the control of rDNA transcription. The exogenous KDM2A with a mutation in the CxxC-ZF domain retained the demethylase activity but did not reduce rDNA transcription on starvation. It was found that the CxxC-ZF domain of KDM2A bound to the rDNA promoter with unmethylated CpG dinucleotides in vitro and in vivo. The exogenous KDM2A with the mutation in the CxxC-ZF domain failed to reduce H3K36me2 in the rDNA promoter on starvation. Further, it was suggested that KDM2A that bound to the rDNA promoter was activated on starvation. Our results demonstrate that KDM2A binds to the rDNA promoter with unmethylated CpG sequences via the CxxC-ZF domain, demethylates H3K36me2 in the rDNA promoter in response to starvation in a JmjC domain-dependent manner, and reduces rDNA transcription.

Zhipeng Fan - One of the best experts on this subject based on the ideXlab platform.

  • Homeobox C8 inhibited the osteo‐/dentinogenic differentiation and migration ability of stem cells of the apical papilla via activating KDM1A
    Journal of Cellular Physiology, 2020
    Co-Authors: Haoqing Yang, Yuncun Liang, Yangyang Cao, Yu Cao, Zhipeng Fan
    Abstract:

    Enhancing the functions of mesenchymal stem cells (MSCs) is considered a potential approach for promoting tissue regeneration. In the present study, we investigate the role of HOXC8 in regulating differentiation and migration by using stem cells of the apical papilla (SCAPs). Our results showed that overexpression of HOXC8 suppressed the osteo-/dentinogenic differentiation, as detected by measuring alkaline phosphatase activity, in vitro mineralization, and the expressions of dentin sialophosphoprotein, dentin matrix acidic phosphoprotein 1, bone sialoprotein, runt-related transcription factor 2, and osterix in SCAPs, and inhibited in vivo osteo-/dentinogenesis of SCAPs. In addition, knockdown of HOXC8 promoted the osteo-/dentinogenic differentiation potentials of SCAPs. Mechanically, HOXC8 enhanced KDM1A transcription by directly binding to its promoter. HOXC8 and KDM1A also inhibited the migration and chemotaxis abilities of SCAPs. To sum up, HOXC8 negatively regulated the osteo-/dentinogenic differentiation and migration abilities of SCAPs by directly enhancing KDM1A transcription and indicated that HOXC8 and KDM1A could serve as potential targets for enhancing dental MSC mediated tissue regeneration.

  • homeobox c8 inhibited the osteo dentinogenic differentiation and migration ability of stem cells of the apical papilla via activating kdm1a
    Journal of Cellular Physiology, 2020
    Co-Authors: Haoqing Yang, Yuncun Liang, Yangyang Cao, Yu Cao, Zhipeng Fan
    Abstract:

    Enhancing the functions of mesenchymal stem cells (MSCs) is considered a potential approach for promoting tissue regeneration. In the present study, we investigate the role of HOXC8 in regulating differentiation and migration by using stem cells of the apical papilla (SCAPs). Our results showed that overexpression of HOXC8 suppressed the osteo-/dentinogenic differentiation, as detected by measuring alkaline phosphatase activity, in vitro mineralization, and the expressions of dentin sialophosphoprotein, dentin matrix acidic phosphoprotein 1, bone sialoprotein, runt-related transcription factor 2, and osterix in SCAPs, and inhibited in vivo osteo-/dentinogenesis of SCAPs. In addition, knockdown of HOXC8 promoted the osteo-/dentinogenic differentiation potentials of SCAPs. Mechanically, HOXC8 enhanced KDM1A transcription by directly binding to its promoter. HOXC8 and KDM1A also inhibited the migration and chemotaxis abilities of SCAPs. To sum up, HOXC8 negatively regulated the osteo-/dentinogenic differentiation and migration abilities of SCAPs by directly enhancing KDM1A transcription and indicated that HOXC8 and KDM1A could serve as potential targets for enhancing dental MSC mediated tissue regeneration.

  • Histone demethylase KDM2B inhibits the chondrogenic differentiation potentials of stem cells from apical papilla.
    International journal of clinical and experimental medicine, 2015
    Co-Authors: Jing-jing Wang, Liping Wang, Rui Dong, Songlin Wang, Jinsong Wang, Zhaochen Shan, Zhipeng Fan
    Abstract:

    Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but the molecular mechanism underlying directed differentiation remains unclear; this has restricted potential MSC applications. Histone methylation, controlled by histone methyltransferases and demethylases, may play a key role in MSCs differentiation. Previous studies determined that KDM2B can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. It is not known whether KDM2B is involved in the other cell lineages differentiation of MSCs. Here we used the stem cells from apical papilla (SCAPs) to study the role of KDM2B on the chondrogenic differentiation potentials in MSCs. In this study, Gain- and loss-of-function assays were applied to investigate the role of KDM2B on the chondrogenic differentiation. Alcian Blue Staining and Quantitative Analysis were used to investigate the synthesis of proteoglycans by chondrocytes. Real-time RT-PCR was used to detect the expressions of chondrogenesis related genes. The Alcian Blue staining and Quantitative Analysis results revealed that overexpression of KDM2B decreased the proteoglycans production, and real-time RT-PCR results showed that the expressions of the chondrogenic differentiation markers, COL1, COL2 and SOX9 were inhibited by overexpression of KDM2B in SCAPs. On the contrary, depletion of KDM2B increased the proteoglycans production, and inhibited the expressions of COL1, COL2 and SOX9. In conclusion, our results indicated that KDM2B is a negative regulator of chondrogenic differentiation in SCAPs and suggest that inhibition of KDM2B might improve MSC mediated cartilage regeneration.

  • depletion of histone demethylase KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of stem cells from apical papilla
    Experimental Cell Research, 2013
    Co-Authors: Rui Dong, Songlin Wang, Rui Yao, Zhipeng Fan
    Abstract:

    Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration, but the molecular mechanism underlying directed differentiation remains unclear; this has restricted potential MSC applications. The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), is evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. A previous study determined that KDM2A can regulate the cell proliferation and osteo/dentinogenic differentiation of MSCs. It is not known whether KDM2A is involved in the other cell lineages differentiation of MSCs. Here, we show that depletion of KDM2A by short hairpin RNAs can enhance adipogenic and chondrogenic differentiation potentials in human stem cells from apical papilla (SCAPs). We found that the stemness-related genes, SOX2, and the embryonic stem cell master transcription factor, NANOG were significantly increased after silence of KDM2A in SCAPs. Moreover, we found that knock-down of the KDM2A co-factor, BCOR also up-regulated the mRNA levels of SOX2 and NANOG. Furthermore, Chromatin immunoprecipitation assays demonstrate that silence of KDM2A increased the histone H3 Lysine 4 (H3K4) trimethylation in the SOX2 and NANOG locus and regulates its expression. In conclusion, our results suggested that depletion of KDM2A enhanced the adipogenic and chondrogenic differentiation potentials of SCAPs by up-regulated SOX2 and NANOG, BCOR also involved in this regulation as co-factor, and provided useful information to understand the molecular mechanism underlying directed differentiation in MSCs.

  • depletion of histone demethylase KDM2A inhibited cell proliferation of stem cells from apical papilla by de repression of p15ink4b and p27kip1
    Molecular and Cellular Biochemistry, 2013
    Co-Authors: Runtao Gao, Rui Dong, Songlin Wang, Zhipeng Fan
    Abstract:

    Mesenchymal stem cells (MSCs) are a reliable resource for tissue regeneration; although, the molecular mechanisms of their differentiation and proliferation are not clearly understood, which restricts the applications of MSCs. The histone demethylase, lysine (K)-specific demethylase 2A (KDM2A), and the mammalian paralog, lysine (K)-specific demethylase 2B (KDM2B), are evolutionarily conserved and ubiquitously expressed members of the JmjC-domain-containing histone demethylase family. A previous study determined that KDM2A and KDM2B can regulate the differentiation of MSCs, and KDM2B has been implicated in cell cycle regulation by de-repressing p15INK4B (cyclin-dependent kinase inhibitor 2B). It is not known whether KDM2A is involved in the cell proliferation of MSCs. Here, we show that depletion of KDM2A by short hairpin RNAs can inhibit cell proliferation and arrest cell cycle progression at the G1/S-phase in human stem cells from apical papilla (SCAPs). The effect of KDM2A on cell proliferation was found to be mediated through de-repression of the cyclin-dependent kinase inhibitors, p15INK4B and p27Kip1 (cyclin-dependent kinase inhibitor 1B), in KDM2A knock-down SCAPs. Furthermore, chromatin immunoprecipitation assays demonstrated that silencing of KDM2A increased histone H3 Lysine 4 (H3K4) trimethylation at the p15INK4B and p27Kip1 loci and regulated its expression. Together, our results indicate that KDM2A is a H3K4 demethylase that regulates cell proliferation through p15INK4B and p27Kip1 in SCAPs.

Songhui Xu - One of the best experts on this subject based on the ideXlab platform.

  • targeting the usp1 dependent kdm4a protein stability as a potential prostate cancer therapy
    Cancer Science, 2020
    Co-Authors: Tianpei Guan, Songhui Xu, Xin-yan Geng, De-xue Fu, Hao-wu Jiang, You-qiang Li
    Abstract:

    The histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability. Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.