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1
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Lee HT, Kim YA, Lee S, Jung YE, Kim H, Kim TW, Kwak S, Kim J, Lee CH, Cha SS, Choi J, Cho EJ, Youn HD. Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells. Nucleic Acids Res 2024; 52:13706-13722. [PMID: 39588763 DOI: 10.1093/nar/gkae1076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 09/24/2024] [Accepted: 11/23/2024] [Indexed: 11/27/2024] Open
Abstract
Cells need to overcome both intrinsic and extrinsic threats. Although pluripotency is associated with damage responses, how stem cells respond to DNA damage remains controversial. Here, we elucidate that DNA damage activates Chk2, leading to the phosphorylation of serine 164 on C-terminal binding protein 2 (Ctbp2). The phosphorylation of Ctbp2 induces the disruption of Ctbp2 tetramer, weakening interactions with zinc finger proteins, leading to the dissociation of phosphorylated Ctbp2 from chromatin. This transition to a monomeric state results in the separation of histone deacetylase 1 from Ctbp2, consequently slowing the rate of H3K27 deacetylation. In contrast to the nucleosome remodeling and deacetylase complex, phosphorylated Ctbp2 increased binding affinity to polycomb repressive complex (PRC)2, interacting through the N-terminal domain of Suz12. Through this domain, Ctbp2 competes with Jarid2, inhibiting the function of PRC2. Thus, the phosphorylation of Ctbp2 under stress conditions represents a precise mechanism aimed at preserving stemness traits by inhibiting permanent transcriptional shutdown.
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Affiliation(s)
- Han-Teo Lee
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea
| | - Young Ah Kim
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sangho Lee
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Ye-Eun Jung
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hanbyeol Kim
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Department of Pharmacology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Tae Wan Kim
- Department of Interdisciplinary Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea
| | - Sojung Kwak
- Developmental Biology Laboratory, Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Jaehyeon Kim
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Chul-Hwan Lee
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea
- Department of Pharmacology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sun-Shin Cha
- Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
- R&D Division, TODD PHARM CO. LTD., Seoul 03760, Republic of Korea
| | - Jinmi Choi
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Eun-Jung Cho
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Hong-Duk Youn
- Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea
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2
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Jung M, Nicholas N, Grindrod S, Dritschilo A. Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth. PLoS One 2024; 19:e0306168. [PMID: 39008483 PMCID: PMC11249239 DOI: 10.1371/journal.pone.0306168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/12/2024] [Indexed: 07/17/2024] Open
Abstract
Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303. Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3. Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 μM, compared to 1.2-2.5 μM for triple negative breast cancer cells, and ~12 μM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.
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Affiliation(s)
- Mira Jung
- Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC, United States of America
| | - Nicole Nicholas
- Department of Biochemistry & Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, DC, United States of America
| | - Scott Grindrod
- Shuttle Pharmaceuticals, Inc., Rockville, Maryland, United States of America
| | - Anatoly Dritschilo
- Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC, United States of America
- Shuttle Pharmaceuticals, Inc., Rockville, Maryland, United States of America
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3
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Shah P, McGuigan CW, Cheng S, Vanpouille-Box C, Demaria S, Weiss RS, Lammerding J. ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels. Front Cell Dev Biol 2022; 10:875132. [PMID: 35721517 PMCID: PMC9198445 DOI: 10.3389/fcell.2022.875132] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/13/2022] [Indexed: 12/18/2022] Open
Abstract
Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations-as found in patients suffering from Ataxia Telangiectasia and many human cancers-which could lead to enhanced cell migration and increased metastatic potential.
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Affiliation(s)
- Pragya Shah
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States
| | - Connor W. McGuigan
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States
| | - Svea Cheng
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States
| | - Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medicine, New York City, NY, United States
| | - Sandra Demaria
- Department of Radiation Oncology, Weill Cornell Medicine, New York City, NY, United States
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York City, NY, United States
| | - Robert S. Weiss
- Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States
| | - Jan Lammerding
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States
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4
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Wang X, Zhao J. Targeted Cancer Therapy Based on Acetylation and Deacetylation of Key Proteins Involved in Double-Strand Break Repair. Cancer Manag Res 2022; 14:259-271. [PMID: 35115826 PMCID: PMC8800007 DOI: 10.2147/cmar.s346052] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/13/2022] [Indexed: 12/22/2022] Open
Abstract
DNA double-strand breaks (DSBs) play an important role in promoting genomic instability and cell death. The precise repair of DSBs is essential for maintaining genome integrity during cancer progression, and inducing genomic instability or blocking DNA repair is an important mechanism through which chemo/radiotherapies exert killing effects on cancer cells. The two main pathways that facilitate the repair of DSBs in cancer cells are homologous recombination (HR) and non-homologous end-joining (NHEJ). Accumulating data suggest that the acetylation and deacetylation of DSB repair proteins regulate the initiation and progression of the cellular response to DNA DSBs, which may further affect the chemosensitivity or radiosensitivity of cancer cells. Here, we focus on the role of acetylation/deacetylation in the regulation of ataxia-telangiectasia mutated, Rad51, and 53BP1 in the HR pathway, as well as the relevant roles of PARP1 and Ku70 in NHEJ. Notably, several histone deacetylase (HDAC) inhibitors targeting HR or NHEJ have been demonstrated to enhance chemo/radiosensitivity in preclinical studies. This review highlights the essential role of acetylation/deacetylation in the regulation of DSB repair proteins, suggesting that HDAC inhibitors targeting the HR or NHEJ pathways that downregulate DNA DSB repair genes may be worthwhile cancer therapeutic agents.
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Affiliation(s)
- Xiwen Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
| | - Jungang Zhao
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
- Correspondence: Jungang Zhao, Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China, Tel/Fax +86 13889311066, Email
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Abstract
Hepatoblastoma (HB) is the predominant primary liver tumor in children. While the prognosis is favorable when the tumor can be resected, the outcome is dismal for patients with progressed HB. Therefore, a better understanding of the molecular mechanisms responsible for HB is imperative for early detection and effective treatment. Sequencing analysis of human HB specimens unraveled the pivotal role of Wnt/β-catenin pathway activation in this disease. Nonetheless, β-catenin activation alone does not suffice to induce HB, implying the need for additional alterations. Perturbations of several pathways, including Hippo, Hedgehog, NRF2/KEAP1, HGF/c-Met, NK-1R/SP, and PI3K/AKT/mTOR cascades and aberrant activation of c-MYC, n-MYC, and EZH2 proto-oncogenes, have been identified in HB, although their role requires additional investigation. Here, we summarize the current knowledge on HB molecular pathogenesis, the relevance of the preclinical findings for the human disease, and the innovative therapeutic strategies that could be beneficial for the treatment of HB patients.
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Affiliation(s)
- Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Antonio Solinas
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Stefano Cairo
- XenTech, Evry, France,Istituto di Ricerca Pediatrica, Padova, Italy
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
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6
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Recent progress on HDAC inhibitors with dual targeting capabilities for cancer treatment. Eur J Med Chem 2020; 208:112831. [DOI: 10.1016/j.ejmech.2020.112831] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 09/05/2020] [Indexed: 12/11/2022]
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7
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Li G, Tian Y, Zhu WG. The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy. Front Cell Dev Biol 2020; 8:576946. [PMID: 33117804 PMCID: PMC7552186 DOI: 10.3389/fcell.2020.576946] [Citation(s) in RCA: 181] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 09/04/2020] [Indexed: 12/14/2022] Open
Abstract
Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (Nε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.
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Affiliation(s)
- Guo Li
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China
| | - Yuan Tian
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China
- Shenzhen Bay Laboratory, Shenzhen, China
| | - Wei-Guo Zhu
- Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China
- Shenzhen Bay Laboratory, Shenzhen, China
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8
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Wang ZF, Sun WY, Yu DH, Zhao Y, Xu HM, He YF, Li HJ. Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway. Int J Oncol 2018; 53:2269-2277. [PMID: 30226600 DOI: 10.3892/ijo.2018.4544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 07/26/2018] [Indexed: 11/06/2022] Open
Abstract
Although radiation therapy is a powerful anticancer modality, radiation- induced stress response and gene expression with adaptive resistance may severely compromise the effectiveness of radiation. The function of rotundic acid (RA) on inducing apoptosis in the human breast cancer cell line MCF-7 has been investigated in a previous study. In the present study, the combined effect of chemotherapy and radiotherapy on reducing side effects was examined. The results of an MTT assay revealed that radiation (0.5, 2 and 10 Gy) effectively inhibit MCF-7 cell viability in a dose-dependent manner, consistent with the effects of RA (2, 5 and 12.5 µM). Interestingly, a lower dose of radiation (1 Gy) combined with RA (5 µM) exhibited a greater inhibition efficiency compared with a high dose of radiation alone. Flow cytometry revealed that radiation combined with RA induced the apoptosis of MCF-7 cells. Using western blotting, it was demonstrated that radiation induced the expression of ataxia-telangiectasia mutated (ATM) and p53 protein, and that RA enhanced this effect. On examining the potential underlying mechanism, it was revealed that radiation and RA combined induce Bcl-2-associated X protein expression and cell apoptosis in MCF-7 cells. An ATM inhibitor was able to restore the effect of radiation and RA on inducing MCF-7 cell apoptosis. These results suggest that the ATM/p53 pathway directly participates in radiation and RA-induced apoptosis in MCF-7 cells. RA has the potential for development as a novel drug for the treatment of human breast cancer combined with radiation therapy, given that the combined side effects are reduced.
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Affiliation(s)
- Zhong-Feng Wang
- Department of Immunity, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wen-Yi Sun
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences in Jilin University, Changchun, Jilin 130021, P.R. China
| | - De-Hai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, Jilin 130000, P.R. China
| | - Hong-Mei Xu
- Department of Obstetrics, The First Hospital, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yu-Fang He
- Institute of Phytochemistry, Jilin Academy of Chinese Medicine Sciences, Changchun, Jilin 130000, P.R. China
| | - Hai-Jun Li
- Department of Immunity, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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9
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Suraweera A, O’Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol 2018; 8:92. [PMID: 29651407 PMCID: PMC5884928 DOI: 10.3389/fonc.2018.00092] [Citation(s) in RCA: 491] [Impact Index Per Article: 70.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 03/16/2018] [Indexed: 01/10/2023] Open
Abstract
Genetic and epigenetic changes in DNA are involved in cancer development and tumor progression. Histone deacetylases (HDACs) are key regulators of gene expression that act as transcriptional repressors by removing acetyl groups from histones. HDACs are dysregulated in many cancers, making them a therapeutic target for the treatment of cancer. Histone deacetylase inhibitors (HDACi), a novel class of small-molecular therapeutics, are now approved by the Food and Drug Administration as anticancer agents. While they have shown great promise, resistance to HDACi is often observed and furthermore, HDACi have shown limited success in treating solid tumors. The combination of HDACi with standard chemotherapeutic drugs has demonstrated promising anticancer effects in both preclinical and clinical studies. In this review, we summarize the research thus far on HDACi in combination therapy, with other anticancer agents and their translation into preclinical and clinical studies. We additionally highlight the side effects associated with HDACi in cancer therapy and discuss potential biomarkers to either select or predict a patient's response to these agents, in order to limit the off-target toxicity associated with HDACi.
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Affiliation(s)
- Amila Suraweera
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
| | - Kenneth J. O’Byrne
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
- Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Derek J. Richard
- School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia
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10
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Li SJ, Liang XY, Li HJ, Yang GZ, Li W, Li Z, Zhou L, Wen X, Yu DH, Cui JW. Low-dose irradiation inhibits proliferation of the p53null type human prostate cancer cells through the ATM/p21 pathway. Int J Mol Med 2017; 41:548-554. [PMID: 29115439 DOI: 10.3892/ijmm.2017.3237] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 10/25/2017] [Indexed: 11/05/2022] Open
Abstract
Low-dose ionizing radiation (LDIR) induces hormesis, exerts an adoptive effect on normal mammalian cells and stimulates cell proliferation; however, this effect is absent in cancer cells. Little is known on the molecular mechanisms underlying this differential response between normal and cancer cells. In the present study, it was demonstrated that the human prostate cancer cell line PC-3 and the normal prostate cell line RWPE-1 exhibited differential biological responses to LDIR. Through cell cycle analyses, it was demonstrated that LDIR inhibited cell growth and arrested the cell cycle at the S and G2/M phases in PC-3 cells, but not in RWPE-1 cells. Using western blotting, it was demonstrated that LDIR at 75 mGy induced the expression of ataxia-telangiectasia mutated (ATM) protein in PC-3 as well as RWPE-1 cells. However, the ATM̸p21 pathway was activated in PC-3, but not in RWPE-1 cells. Although the expression of p53 was not affected by 75 mGy LDIR in RWPE-1 cells, the ATM̸p21 pathway was activated when RWPE-1 cells lost p53 function. In addition, when using ATM inhibitors, the ATM̸p21 pathway was inactivated in both cell lines, and the LDIR-induced cell proliferation inhibition was also abolished. These findings suggested that the ATM/p21 pathway directly participated in the LDIR-induced cell proliferation inhibition in p53null type prostate tumor cells, whereas this mechanism was absent in normal prostate cells. Thus, p53 may affect cell stability following LDIR, and plays a crucial role in regulating the ATM/p21 pathway activated by LDIR.
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Affiliation(s)
- Si-Jie Li
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xin-Yue Liang
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hai-Jun Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Guo-Zi Yang
- Department of Radiation-Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zhuo Li
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Lei Zhou
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xue Wen
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - De-Hai Yu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Jiu-Wei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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11
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Roos WP, Krumm A. The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair. Nucleic Acids Res 2016; 44:10017-10030. [PMID: 27738139 PMCID: PMC5137451 DOI: 10.1093/nar/gkw922] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 10/02/2016] [Accepted: 10/05/2016] [Indexed: 12/16/2022] Open
Abstract
Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD+ dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD+, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization.
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Affiliation(s)
- Wynand Paul Roos
- Institute of Toxicology, Medical Center of the University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany
| | - Andrea Krumm
- Institute of Toxicology, Medical Center of the University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany
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12
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Eliopoulos AG, Havaki S, Gorgoulis VG. DNA Damage Response and Autophagy: A Meaningful Partnership. Front Genet 2016; 7:204. [PMID: 27917193 PMCID: PMC5116470 DOI: 10.3389/fgene.2016.00204] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 11/02/2016] [Indexed: 01/07/2023] Open
Abstract
Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein, we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies.
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Affiliation(s)
- Aristides G Eliopoulos
- Molecular and Cellular Biology Laboratory, Division of Basic Sciences, Medical School, University of CreteHeraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology HellasHeraklion, Greece
| | - Sophia Havaki
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens Athens, Greece
| | - Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of AthensAthens, Greece; Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of ManchesterManchester, UK; Biomedical Research Foundation of the Academy of AthensAthens, Greece
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13
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Park JS, Na HJ, Pyo JH, Jeon HJ, Kim YS, Yoo MA. Requirement of ATR for maintenance of intestinal stem cells in aging Drosophila. Aging (Albany NY) 2016; 7:307-18. [PMID: 26000719 PMCID: PMC4468312 DOI: 10.18632/aging.100743] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The stem cell genomic stability forms the basis for robust tissue homeostasis, particularly in high-turnover tissues. For the genomic stability, DNA damage response (DDR) is essential. This study was focused on the role of two major DDR-related factors, ataxia telangiectasia-mutated (ATM) and ATM- and RAD3-related (ATR) kinases, in the maintenance of intestinal stem cells (ISCs) in the adult Drosophila midgut. We explored the role of ATM and ATR, utilizing immunostaining with an anti-pS/TQ antibody as an indicator of ATM/ATR activation, γ-irradiation as a DNA damage inducer, and the UAS/GAL4 system for cell type-specific knockdown of ATM, ATR, or both during adulthood. The results showed that the pS/TQ signals got stronger with age and after oxidative stress. The pS/TQ signals were found to be more dependent on ATR rather than on ATM in ISCs/enteroblasts (EBs). Furthermore, an ISC/EB-specific knockdown of ATR, ATM, or both decreased the number of ISCs and oxidative stress-induced ISC proliferation. The phenotypic changes that were caused by the ATR knockdown were more pronounced than those caused by the ATM knockdown; however, our data indicate that ATR and ATM are both needed for ISC maintenance and proliferation; ATR seems to play a bigger role than does ATM.
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Affiliation(s)
- Joung-Sun Park
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
| | - Hyun-Jin Na
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
| | - Jung-Hoon Pyo
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
| | - Ho-Jun Jeon
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
| | - Young-Shin Kim
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
| | - Mi-Ae Yoo
- Department of Molecular Biology, Pusan National University, Busan, 609-735, Republic of Korea
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14
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Wang JY, Chen SY, Sun CN, Chien T, Chern Y. A central role of TRAX in the ATM-mediated DNA repair. Oncogene 2016; 35:1657-1670. [PMID: 26096928 DOI: 10.1038/onc.2015.228] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 05/04/2015] [Accepted: 05/18/2015] [Indexed: 12/21/2022]
Abstract
DNA repair is critical for the maintenance of genome stability. Upon genotoxic stress, dysregulated DNA repair may induce apoptosis. Translin-associated factor X (TRAX), which was initially identified as a binding partner of Translin, has been implicated in genome stability. However, the exact role of TRAX in DNA repair remains largely unknown. Here, we showed that TRAX participates in the ATM/H2AX-mediated DNA repair machinery by interacting with ATM and stabilizing the MRN complex at double-strand breaks. The exogenous expression of wild-type (WT) TRAX, but not a TRAX variant lacking the nuclear localization signal (NLS), rescued the vulnerability of TRAX-null mouse embryo fibroblasts (MEFs). This finding confirms the importance of the nuclear localization of TRAX in the repair of DNA damage. Compared with WT MEFs, TRAX-null MEFs exhibited impaired DNA repair (for example, reduced phosphorylation of ATM and H2AX) after treatment with ultra violet-C or γ-ray irradiation and a higher incidence of p53-mediated apoptosis. Our findings demonstrate that TRAX is required for MRN complex-ATM-H2AX signaling, which optimizes DNA repair by interacting with the activated ATM and protects cells from genotoxic stress-induced apoptosis.
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Affiliation(s)
- J-Y Wang
- Department of Neurology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - S-Y Chen
- Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - C-N Sun
- Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - T Chien
- Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Y Chern
- Neuroscience Division, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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15
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Kim JH, Moon SH, No M, Kim JJ, Choi EJ, Cho BJ, Kim JS, Kim IH, Kim IA. Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization. Cancer Res Treat 2015; 48:1130-40. [PMID: 26582395 PMCID: PMC4946349 DOI: 10.4143/crt.2015.206] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 11/01/2015] [Indexed: 12/12/2022] Open
Abstract
Purpose Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity. Materials and Methods Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhibit HDAC in an isotype-specific manner. Radiation cell survival was evaluated using a clonogenic assay in SQ20B cells transfected with small interfering RNA specifically targeting HDAC isotypes. Immunocytochemistry was performed for detection of γH2AX foci. Protein expression was measured using Western blotting. Results Among 11 HDAC isotypes tested, specific inhibition of 7 isotypes (HDAC1, HDAC3, HDAC4, HDAC6, HDAC7, HDAC10, and HDAC11) enhanced radiation lethality in SQ20B cells. Radiosensitization by inhibition of these HDAC isotypes was accompanied by delay of DNA double strand break repair. Radiosensitivity of SQ20B cells was not altered by selective inhibition of the remaining four isotypes (HDAC2, HDAC5, HDAC8, and HDAC9). Inhibition of HDAC isotypes resulted in downregulation of various proteins involved in pro-survival and DNA damage repair pathways. Conclusion Isotype-specificity exists in HDAC inhibition-induced radiosensitization. Different HDAC isotypes are differentially involved in modulation of cellular radiosensitivity.
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Affiliation(s)
- Jin Ho Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea
| | - Sung Ho Moon
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Mina No
- Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Jin Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Jung Choi
- Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bong Jun Cho
- Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Sung Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Il Han Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - In Ah Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea.,Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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16
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Stengel KR, Hiebert SW. Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy. Antioxid Redox Signal 2015; 23:51-65. [PMID: 24730655 PMCID: PMC4492608 DOI: 10.1089/ars.2014.5915] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
SIGNIFICANCE The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear. RECENT ADVANCES While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy. CRITICAL ISSUES Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment. FUTURE DIRECTIONS Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain.
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Affiliation(s)
- Kristy R. Stengel
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Scott W. Hiebert
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
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17
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Cao LL, Wei F, Du Y, Song B, Wang D, Shen C, Lu X, Cao Z, Yang Q, Gao Y, Wang L, Zhao Y, Wang H, Yang Y, Zhu WG. ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. Oncogene 2015; 35:301-13. [DOI: 10.1038/onc.2015.81] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 01/21/2015] [Accepted: 02/22/2015] [Indexed: 12/25/2022]
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18
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Zhu Q, Battu A, Ray A, Wani G, Qian J, He J, Wang QE, Wani AA. Damaged DNA-binding protein down-regulates epigenetic mark H3K56Ac through histone deacetylase 1 and 2. Mutat Res 2015; 776:16-23. [PMID: 26255936 DOI: 10.1016/j.mrfmmm.2015.01.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 12/09/2014] [Accepted: 01/17/2015] [Indexed: 12/12/2022]
Abstract
Acetylated histone H3 lysine 56 (H3K56Ac) is one of the reversible histone post-translational modifications (PTMs) responsive to DNA damage. We previously described a biphasic decrease and increase of epigenetic mark H3K56Ac in response to ultraviolet radiation (UVR)-induced DNA damage. Here, we report a new function of UV damaged DNA-binding protein (DDB) in deacetylation of H3K56Ac through specific histone deacetylases (HDACs). We show that simultaneous depletion of HDAC1/2 compromises the deacetylation of H3K56Ac, while depletion of HDAC1 or HDAC2 alone has no effect on H3K56Ac. The H3K56Ac deacetylation does not require functional nucleotide excision repair (NER) factors XPA and XPC, but depends on the function of upstream factors DDB1 and DDB2. UVR enhances the association of DDB2 with HDAC1 and, enforced DDB2 expression leads to translocation of HDAC1 to UVR-damaged chromatin. HDAC1 and HDAC2 are recruited to UVR-induced DNA damage spots, which are visualized by anti-XPC immunofluorescence. Dual HDAC1/2 depletion decreases XPC ubiquitination, but does not affect the recruitment of DDB2 to DNA damage. By contrast, the local accumulation of γH2AX at UVR-induced DNA damage spots was compromised upon HDAC1 as well as dual HDAC1/2 depletions. Additionally, UVR-induced ATM activation decreased in H12899 cells expressing H3K56Ac-mimicing H3K56Q. These results revealed a novel role of DDB in H3K56Ac deacetylation during early step of NER and the existence of active functional cross-talk between DDB-mediated damage recognition and H3K56Ac deacetylation.
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Affiliation(s)
- Qianzheng Zhu
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Aruna Battu
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Alo Ray
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Gulzar Wani
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Jiang Qian
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Jinshan He
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Qi-en Wang
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States
| | - Altaf A Wani
- Department of Radiology, The Ohio State University, Columbus, OH 43210, United States; Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, United States; James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH 43210, United States.
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19
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Czarny P, Pawlowska E, Bialkowska-Warzecha J, Kaarniranta K, Blasiak J. Autophagy in DNA damage response. Int J Mol Sci 2015; 16:2641-62. [PMID: 25625517 PMCID: PMC4346856 DOI: 10.3390/ijms16022641] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 01/12/2015] [Indexed: 12/15/2022] Open
Abstract
DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, although it is suggested that it involves the inhibition of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 represses autophagy via phosphorylation of the ULK1/2-Atg13-FIP200 complex thus preventing maturation of pre-autophagosomal structures. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly(ADP)ribose polymerase 1 (PARP-1), Mre11-Rad50-Nbs1 (MRN) complex or FOXO3, which activate repressors of mTORC1. SQSTM1/p62 is one of the proteins whose levels are regulated via autophagic degradation. Inhibition of autophagy by knockout of FIP200 results in upregulation of SQSTM1/p62, enhanced DNA damage and less efficient damage repair. Mitophagy, one form of autophagy involved in the selective degradation of mitochondria, may also play role in DDR. It degrades abnormal mitochondria and can either repress or activate apoptosis, but the exact mechanism remains unknown. There is a need to clarify the role of autophagy in DDR, as this process may possess several important biomedical applications, involving also cancer therapy.
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Affiliation(s)
- Piotr Czarny
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
| | - Elzbieta Pawlowska
- Department of Orthodontics, Medical University of Lodz, Pomorska 251, 92-216 Lodz, Poland.
| | - Jolanta Bialkowska-Warzecha
- Department of Infectious and Liver Diseases, Medical University of Lodz, Kniaziewicza 1/5, 92-347 Lodz, Poland.
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio FI-70211, Finland.
| | - Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
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20
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Abramova MV, Svetlikova SB, Kukushkin AN, Aksenov ND, Pospelova TV, Pospelov VA. HDAC inhibitor sodium butyrate sensitizes E1A+Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of γH2AX foci. Cancer Biol Ther 2014; 12:1069-77. [DOI: 10.4161/cbt.12.12.18365] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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21
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Bose P, Dai Y, Grant S. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. Pharmacol Ther 2014; 143:323-336. [PMID: 24769080 PMCID: PMC4117710 DOI: 10.1016/j.pharmthera.2014.04.004] [Citation(s) in RCA: 209] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 04/10/2014] [Indexed: 02/05/2023]
Abstract
Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.
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Affiliation(s)
- Prithviraj Bose
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Yun Dai
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven Grant
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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22
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Li Z, Zhu WG. Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int J Biol Sci 2014; 10:757-70. [PMID: 25013383 PMCID: PMC4081609 DOI: 10.7150/ijbs.9067] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/02/2014] [Indexed: 12/19/2022] Open
Abstract
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications.
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Affiliation(s)
- Zhiming Li
- 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100191, China. ; 2. Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China
| | - Wei-Guo Zhu
- 1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing 100191, China. ; 2. Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, 100191, China. ; 3. Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing 100871, China
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23
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Kim JH, Kim IH, Shin JH, Kim HJ, Kim IA. Sequence-Dependent Radiosensitization of Histone Deacetylase Inhibitors Trichostatin A and SK-7041. Cancer Res Treat 2013; 45:334-42. [PMID: 24454006 PMCID: PMC3893331 DOI: 10.4143/crt.2013.45.4.334] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Accepted: 04/29/2013] [Indexed: 11/21/2022] Open
Abstract
PURPOSE This preclinical study is to determine whether the capacity of histone deacetylase (HDAC) inhibitors to enhance radiation response depends on temporal sequences of HDAC inhibition and irradiation. MATERIALS AND METHODS The effects of HDAC inhibitors trichostatin A (TSA) and SK-7041 on radiosensitivity in human lung cancer cells were examined using a clonogenic assay, exposing cells to HDAC inhibitors in various sequences of HDAC inhibition and radiation. We performed Western blot of acetylated histone H3 and flow cytometry to analyze cell cycle phase distribution. RESULTS TSA and SK-7041 augmented radiation cell lethality in an exposure time-dependent manner when delivered before irradiation. The impact of TSA and SK-7041 on radiosensitivity rapidly diminished when HDAC inhibition was delayed after irradiation. Radiation induced the acetylation of histone H3 in cells exposed to TSA, while irradiation alone had no effect on the expression of acetylated histone H3 in TSA-naïve cells. Preirradiation exposure to TSA abrogated radiation-induced G2/M-phase arrest. When delivered after irradiation, TSA had no effect on the peak of radiation-induced G2/M-phase arrest. CONCLUSION TSA and SK-7041 enhances radiosensitivity only when delivered before irradiation. Unless proven otherwise, it seems prudent to apply scheduling including preirradiation HDAC inhibition so that maximal radiosensitization is obtained.
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Affiliation(s)
- Jin Ho Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Il Han Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea
| | - Jin Hee Shin
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Hak Jae Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - In Ah Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. ; Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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24
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Thurn KT, Thomas S, Raha P, Qureshi I, Munster PN. Histone deacetylase regulation of ATM-mediated DNA damage signaling. Mol Cancer Ther 2013; 12:2078-87. [PMID: 23939379 DOI: 10.1158/1535-7163.mct-12-1242] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.
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Affiliation(s)
- K Ted Thurn
- Corresponding Author: Pamela N. Munster, Division of Hematology and Oncology, Department of Medicine, University of California, 1600 Divisadero, Room A719, Box 1711, San Francisco, CA 94143.
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25
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Abstract
Histone deacetylase inhibitors (HDACis) increase gene expression through induction of histone acetylation. However, it remains unclear whether specific gene expression changes determine the apoptotic response following HDACis administration. Herein, we discuss evidence that HDACis trigger in cancer and leukemia cells not only widespread histone acetylation but also actual increases in reactive oxygen species (ROS) and DNA damage that are further increased following treatment with DNA-damaging chemotherapies. While the origins of ROS production are not completely understood, mechanisms, including inflammation and altered antioxidant signaling, have been reported. While the generation of ROS is an explanation, at least in part, for the source of DNA damage observed with HDACi treatment, DNA damage can also be independently induced by changes in the DNA repair activity and chromatin remodeling factors. Recent development of sirtuin inhibitors (SIRTis) has shown that, similar to HDACis, these drugs induce increases in ROS and DNA damage used singly, or in combination with HDACis and other drugs. Thus, induction of apoptosis by HDACis/SIRTis may result through oxidative stress and DNA damage mechanisms in addition to direct activation of apoptosis-inducing genes. Nevertheless, while DNA damage and stress responses could be of interest as markers for clinical responses, they have yet to be validated as markers for responses to HDACi treatment in clinical trials, alone, and in combination.
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Affiliation(s)
- Carine Robert
- Department of Radiation Oncology and Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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26
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Abstract
DNA damage detection and repair take place in the context of chromatin, and histone proteins play important roles in these events. Post-translational modifications of histone proteins are involved in repair and DNA damage signalling processes in response to genotoxic stresses. In particular, acetylation of histones H3 and H4 plays an important role in the mammalian and yeast DNA damage response and survival under genotoxic stress. However, the role of post-translational modifications to histones during the plant DNA damage response is currently poorly understood. Several different acetylated H3 and H4 N-terminal peptides following X-ray treatment were identified using MS analysis of purified histones, revealing previously unseen patterns of histone acetylation in Arabidopsis. Immunoblot analysis revealed an increase in the relative abundance of the H3 acetylated N-terminus, and a global decrease in hyperacetylation of H4 in response to DNA damage induced by X-rays. Conversely, mutants in the key DNA damage signalling factor ATM (ATAXIA TELANGIECTASIA MUTATED) display increased histone acetylation upon irradiation, linking the DNA damage response with dynamic changes in histone modification in plants.
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27
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Thompson LH. Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: the molecular choreography. Mutat Res 2012; 751:158-246. [PMID: 22743550 DOI: 10.1016/j.mrrev.2012.06.002] [Citation(s) in RCA: 261] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 06/09/2012] [Accepted: 06/16/2012] [Indexed: 12/15/2022]
Abstract
The faithful maintenance of chromosome continuity in human cells during DNA replication and repair is critical for preventing the conversion of normal diploid cells to an oncogenic state. The evolution of higher eukaryotic cells endowed them with a large genetic investment in the molecular machinery that ensures chromosome stability. In mammalian and other vertebrate cells, the elimination of double-strand breaks with minimal nucleotide sequence change involves the spatiotemporal orchestration of a seemingly endless number of proteins ranging in their action from the nucleotide level to nucleosome organization and chromosome architecture. DNA DSBs trigger a myriad of post-translational modifications that alter catalytic activities and the specificity of protein interactions: phosphorylation, acetylation, methylation, ubiquitylation, and SUMOylation, followed by the reversal of these changes as repair is completed. "Superfluous" protein recruitment to damage sites, functional redundancy, and alternative pathways ensure that DSB repair is extremely efficient, both quantitatively and qualitatively. This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR). The exponential growth of molecular studies, heavily driven by RNA knockdown technology, now reveals an outline of how many key protein players in genome stability and cancer biology perform their interwoven tasks, e.g. ATM, ATR, DNA-PK, Chk1, Chk2, PARP1/2/3, 53BP1, BRCA1, BRCA2, BLM, RAD51, and the MRE11-RAD50-NBS1 complex. Thus, the nature of the intricate coordination of repair processes with cell cycle progression is becoming apparent. This review also links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships.
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Affiliation(s)
- Larry H Thompson
- Biology & Biotechnology Division, L452, Lawrence Livermore National Laboratory, P.O. Box 808, Livermore, CA 94551-0808, United States.
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28
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Miller AC, Cohen S, Stewart M, Rivas R, Lison P. Radioprotection by the histone deacetylase inhibitor phenylbutyrate. RADIATION AND ENVIRONMENTAL BIOPHYSICS 2011; 50:585-596. [PMID: 21892632 DOI: 10.1007/s00411-011-0384-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2011] [Accepted: 08/15/2011] [Indexed: 05/31/2023]
Abstract
The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel anti-tumor agent. Studies have demonstrated that HDAC inhibitors can suppress cutaneous radiation syndrome and stimulate hematopoiesis. The objective of this study was to test the ability of PB treatment to protect against acute gamma-radiation-induced lethality in the DBA/2 mouse model. A 30-day radiation lethality study was used to assess radioprotective capability of PB. Mechanisms were evaluated using western blots, flow cytometry, and the single-cell gel electrophoresis assay. Western blot studies showed that PB treatment acetylated histones in vivo. For radiation protection studies, prophylactic administration of PB (24 h preradiation; 1-50 mg/kg) provided radioprotection against gamma radiation (8-9.5 Gy) and PB demonstrated a DRF of 1.31 (P = 0.001; 95% confidence interval: 1.27, 1.36). When PB (10 mg/kg) was administered post-radiation (4 h), it also provided significant radioprotection at 8.0 Gy radiation (P = 0.022). PB treatment before radiation was associated with significant elevations in neutrophils and platelets following radiation. Results from single-cell gel electrophoresis of peripheral blood leukocytes demonstrated that PB treatment before radiation can attenuate DNA damage and inhibit radiation-induced apoptosis. These results indicate that an HDAC inhibitor like PB has potential as a radiation protector and that mechanisms of action include attenuation of DNA damage and inhibition of apoptosis.
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Affiliation(s)
- Alexandra C Miller
- Scientific Research Department, Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University, Bethesda, MD 20889-5603, USA.
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29
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Rajendran P, Ho E, Williams DE, Dashwood RH. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenetics 2011; 3:4. [PMID: 22247744 PMCID: PMC3255482 DOI: 10.1186/1868-7083-3-4] [Citation(s) in RCA: 142] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 10/26/2011] [Indexed: 12/21/2022] Open
Abstract
Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies.
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Affiliation(s)
- Praveen Rajendran
- Cancer Chemoprotection Program, Linus Pauling Institute, 307 Linus Pauling Science Center, Oregon State University, Corvallis OR 97331, USA
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Nambiar D, Rajamani P, Singh RP. Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy. Mutat Res 2011; 728:139-57. [PMID: 22030216 DOI: 10.1016/j.mrrev.2011.07.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Revised: 07/27/2011] [Accepted: 07/28/2011] [Indexed: 02/01/2023]
Abstract
Ionizing radiation (IR)-induced cellular damage is implicated in carcinogenesis as well as therapy of cancer. Advances in radiation therapy have led to the decrease in dosage and localizing the effects to the tumor; however, the development of radioresistance in cancer cells and radiation toxicity to normal tissues are still the major concerns. The development of radioresistance involves several mechanisms, including the activation of mitogenic and survival signaling, induction of DNA repair, and changes in redox signaling and epigenetic regulation. The current strategy of combining radiation with standard cytotoxic chemotherapeutic agents can potentially lead to unwanted side effects due to both agents. Thus agents are needed that could improve the efficacy of radiation killing of cancer cells and prevent the damage to normal cells and tissues caused by the direct and bystander effects of radiation, without have its own systemic toxicity. Chemopreventive phytochemicals, usually non-toxic agents with both cancer preventive and therapeutic activities, could rightly fit in this approach. In this regard, naturally occurring compounds, including curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin and resveratrol, have shown considerable potential. These agents suppress the radiation-induced activation of receptor tyrosine kinases and nuclear factor-κB signaling, can modify cell survival and DNA repair efficacy, and may potentiate ceramide signaling. These radiosensitizing and counter radioresistance mechanisms of phytochemicals in cancer cells are also associated with changes in epigenetic gene regulation. Because radioresistance involves multiple mechanisms, more studies are needed to discover novel phytochemicals having multiple mechanisms of radiosensitization and to overcome radioresistance of cancer cells. Pre-clinical studies are needed to address the appropriate dosage, timing, and duration of the application of phytochemicals with radiation to justify clinical trials. Nonetheless, some phytochemicals in combination with IR may play a significant role in enhancing the therapeutic index of cancer treatment.
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Affiliation(s)
- Dhanya Nambiar
- Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
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31
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Mungenast AE, Tsai LH. Addressing the complex etiology of Alzheimer’s disease: the role of p25/Cdk5. FUTURE NEUROLOGY 2011. [DOI: 10.2217/fnl.11.22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by the progressive loss of forebrain neurons and the deterioration of learning and memory. Therapies for AD have primarily focused upon either the inhibition of amyloid synthesis or its deposition in the brain, but clinical testing to date has not yet found an effective amelioration of cognitive symptoms. Synaptic loss closely correlates with the degree of dementia in AD patients. However, mouse AD models that target the amyloid-β pathway generally do not exhibit a profound loss of synapses, despite extensive synaptic dysfunction. The increased generation of p25, an activator of the cyclin-dependent kinase 5 (Cdk5) has been found in both human patients and mouse models of neurodegeneration. The current work reviews our knowledge, to date, on the role of p25/Cdk5 in Alzheimer’s disease, with a focus upon the interaction of amyloid-β and p25/Cdk5 in synaptic dysfunction and neuronal loss.
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Affiliation(s)
- Alison E Mungenast
- Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Li-Huei Tsai
- Department of Brain & Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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32
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Rodriguez-Rocha H, Aracely-Garcia-Garcia, Panayiotidis MI, Franco R. DNA damage and autophagy. Mutat Res 2011; 711:158-66. [PMID: 21419786 PMCID: PMC3105359 DOI: 10.1016/j.mrfmmm.2011.03.007] [Citation(s) in RCA: 152] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 03/04/2011] [Accepted: 03/11/2011] [Indexed: 12/15/2022]
Abstract
Both exogenous and endogenous agents are a threat to DNA integrity. Exogenous environmental agents such as ultraviolet (UV) and ionizing radiation, genotoxic chemicals and endogenous byproducts of metabolism including reactive oxygen species can cause alterations in DNA structure (DNA damage). Unrepaired DNA damage has been linked to a variety of human disorders including cancer and neurodegenerative disease. Thus, efficient mechanisms to detect DNA lesions, signal their presence and promote their repair have been evolved in cells. If DNA is effectively repaired, DNA damage response is inactivated and normal cell functioning resumes. In contrast, when DNA lesions cannot be removed, chronic DNA damage triggers specific cell responses such as cell death and senescence. Recently, DNA damage has been shown to induce autophagy, a cellular catabolic process that maintains a balance between synthesis, degradation, and recycling of cellular components. But the exact mechanisms by which DNA damage triggers autophagy are unclear. More importantly, the role of autophagy in the DNA damage response and cellular fate is unknown. In this review we analyze evidence that supports a role for autophagy as an integral part of the DNA damage response.
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Affiliation(s)
- Humberto Rodriguez-Rocha
- Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences. University of Nebraska-Lincoln. Lincoln, NE 68583
| | - Aracely-Garcia-Garcia
- Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences. University of Nebraska-Lincoln. Lincoln, NE 68583
| | | | - Rodrigo Franco
- Redox Biology Center and School of Veterinary Medicine and Biomedical Sciences. University of Nebraska-Lincoln. Lincoln, NE 68583
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Thurn KT, Thomas S, Moore A, Munster PN. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol 2011; 7:263-83. [PMID: 21345145 PMCID: PMC3127396 DOI: 10.2217/fon.11.2] [Citation(s) in RCA: 188] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach.
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Affiliation(s)
- K Ted Thurn
- Department of Medicine, Hematology/Oncology Division. University of California, San Francisco, CA, USA
| | - Scott Thomas
- Department of Medicine, Hematology/Oncology Division. University of California, San Francisco, CA, USA
| | - Amy Moore
- Department of Medicine, Hematology/Oncology Division. University of California, San Francisco, CA, USA
| | - Pamela N Munster
- Department of Medicine, Hematology/Oncology Division. University of California, San Francisco, CA, USA
- Author for correspondence: 1600 Divisadero St, Room A722, Box 1770, San Francisco, CA 94115, USA Tel.: +1 415 885 7810 Fax: +1 415 353 7779
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34
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Averbeck NB, Durante M. Protein acetylation within the cellular response to radiation. J Cell Physiol 2011; 226:962-7. [DOI: 10.1002/jcp.22466] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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35
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Histone deacetylase inhibitor: antineoplastic agent and radiation modulator. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 720:171-9. [PMID: 21901627 DOI: 10.1007/978-1-4614-0254-1_14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Inhibitors of histone deacetylases (HDACs) have emerged as a new class of anticancer agents based on their actions in cancer cell growth and cell cycle arrest, terminal differentiation, and apoptosis. Previously, we rationally designed and developed a new class of hydroxamide- and mercaptoacetamide-bearing HDAC inhibitors. A subset of these inhibitors exhibited chemo-radiation sensitizing properties in various human cancer cells. Furthermore, some HDAC inhibitors protected normal cells from radiation-induced damage and extended the survival of mice following total body exposure to lethal dose radiation. Pathological analyses revealed that intestinal and bone marrow cellularities recovered significantly from radiation-induced damage by structural compartments restoration, suggesting the mechanism of action of these HDAC inhibitors. These findings support the hypothesis that epigenetic regulation may play a crucial role in the functional recovery of normal tissues from radiation injuries.
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36
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Jang ER, Choi JD, Park MA, Jeong G, Cho H, Lee JS. ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response. Exp Mol Med 2010; 42:195-204. [PMID: 20164679 DOI: 10.3858/emm.2010.42.3.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45 genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM(+) cells, but not in isogenic ATM(-) or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1- dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45 through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors.
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Affiliation(s)
- Eun Ryoung Jang
- Department of Molecular Science and Technology, College of Natural Sciences, Ajou University, Suwon 443-749, Korea
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37
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Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S, Jackson SP. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nat Struct Mol Biol 2010; 17:1144-51. [PMID: 20802485 DOI: 10.1038/nsmb.1899] [Citation(s) in RCA: 506] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2010] [Accepted: 07/20/2010] [Indexed: 12/18/2022]
Abstract
DNA double-strand break (DSB) repair occurs within chromatin and can be modulated by chromatin-modifying enzymes. Here we identify the related human histone deacetylases HDAC1 and HDAC2 as two participants in the DNA-damage response. We show that acetylation of histone H3 Lys56 (H3K56) was regulated by HDAC1 and HDAC2 and that HDAC1 and HDAC2 were rapidly recruited to DNA-damage sites to promote hypoacetylation of H3K56. Furthermore, HDAC1- and 2-depleted cells were hypersensitive to DNA-damaging agents and showed sustained DNA-damage signaling, phenotypes that reflect defective DSB repair, particularly by nonhomologous end-joining (NHEJ). Collectively, these results show that HDAC1 and HDAC2 function in the DNA-damage response by promoting DSB repair and thus provide important insights into the radio-sensitizing effects of HDAC inhibitors that are being developed as cancer therapies.
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Affiliation(s)
- Kyle M Miller
- The Gurdon Institute, University of Cambridge, Cambridge, UK
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38
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Singh S, Le H, Shih SJ, Ho B, Vaughan AT. Suberoylanilide hydroxyamic acid modification of chromatin architecture affects DNA break formation and repair. Int J Radiat Oncol Biol Phys 2010; 76:566-73. [PMID: 20117292 DOI: 10.1016/j.ijrobp.2009.08.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 08/14/2009] [Accepted: 08/17/2009] [Indexed: 11/18/2022]
Abstract
PURPOSE Chromatin-modifying compounds that inhibit the activity of histone deacetylases have shown potency as radiosensitizers, but the action of these drugs at a molecular level is not clear. Here we investigated the effect of suberoylanilide hydroxyamic acid (SAHA) on DNA breaks and their repair and induction of rearrangements. METHODS AND MATERIALS The effect of SAHA on both clonogenic survival and repair was assessed using cell lines SCC-25, MCF7, and TK6. In order to study unique DNA double-strand breaks, anti-CD95 antibody was employed to introduce a DNA double-strand break at a known location within the 11q23 region. The effects of SAHA on DNA cleavage and rearrangements were analyzed by ligation-mediated PCR and inverse PCR, respectively. RESULTS SAHA acts as radiosensitizer at 1 microM, with dose enhancement factors (DEFs) at 10% survival of: SCC-25 - 1.24 +/- 0.05; MCF7 - 1.16 +/- 0.09 and TK6 - 1.17 +/- 0.05, and it reduced the capacity of SCC-25 cells to repair radiation induced lesions. Additionally, SAHA treatment diffused site-specific fragmentation over at least 1 kbp in TK6 cells. Chromosomal rearrangements produced in TK6 cells exposed to SAHA showed a reduction in microhomology at the breakpoint between 11q23 and partner chromosomes. CONCLUSIONS SAHA shows efficacy as a radiosensitizer at clinically obtainable levels. In its presence, targeted DNA strand breaks occur over an expanded region, indicating increased chromatin access. The rejoining of such breaks is degraded by SAHA when measured as rearrangements at the molecular level and rejoining that contributes to cell survival.
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Affiliation(s)
- Sheetal Singh
- Department of Radiation Oncology, University of California at Davis, 4501 X St., Sacramento, California 95817, USA
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39
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Li Z, Zhang Q, Mao JH, Weise A, Mrasek K, Fan X, Zhang X, Liehr T, Lu KH, Balmain A, Cai WW. An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis. Oncogene 2010; 29:2659-71. [DOI: 10.1038/onc.2010.19] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Kim IA, Kim IH, Kim HJ, Chie EK, Kim JS. HDAC inhibitor-mediated radiosensitization in human carcinoma cells: a general phenomenon? JOURNAL OF RADIATION RESEARCH 2010; 51:257-263. [PMID: 20505264 DOI: 10.1269/jrr.09115] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Histone deacetylase inhibitors (HDIs) have attracted considerable attention for anticancer therapy strategy, including radiosensitization. Regarding a potential application of HDI as a radiosensitizer in the treatment of solid tumors, an important question is whether treatment efficacy would be influenced by intrinsic differences between cancer cells, such as different histologic origin and status of ATM or p53. First we have observed the in vitro radiosensitization by Trichostatin A (TSA) on the broad spectrum of human tumor cell lines having different histologic origin such as HCT116 adenocarcinoma of colon, A549 adenocarcinoma of lung, HN-3 squamous cell carcinoma of head/neck, and HeLa squamous carcinoma of uterine cervix, using clonogenic assay. Next, we have systematically assessed the radiosensitization on the cell lines having different ATM or p53 status. We found that pretreatment of HDI consistently resulted in radiosensitization of all cell lines tested, though the sensitizer enhancement ratio of individual cell lines was variable. We also observed that TSA-mediated radiosensitization was clearly influenced by p53 and ATM status of cells tested. The data presented here indicate that HDI enhances the radiation induced cell killing in the various cancer cells having intrinsic differences and may serve as a general strategy for enhancing tumor cell radiosensitivity. These results have potential implications for the clinical utility of HDI in increasing the anticancer efficacy of radiation.
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Affiliation(s)
- In Ah Kim
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
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41
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Affiliation(s)
- Philip J Tofilon
- Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
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42
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Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 2009; 280:201-10. [PMID: 19181442 DOI: 10.1016/j.canlet.2009.01.002] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2008] [Revised: 12/22/2008] [Accepted: 01/01/2009] [Indexed: 12/31/2022]
Abstract
Vorinostat is a potent histone deacetylase inhibitor that blocks the catalytic site of these enzymes. A large number of cellular proteins are modified post-translationally by acetylation, leading to altered structure and/or function. Many of these proteins, such as core nucleosomal histones and transcription factors, function in key cellular processes and signal transduction pathways that regulate cell growth, migration, and differentiation. At concentrations that are non-toxic to normal cells, vorinostat dramatically alters cellular acetylation patterns and causes growth arrest and death and in a wide range of transformed cells, both in vitro and in animal tumor models. Vorinostat has shown promising clinical activity against hematologic and solid tumors at doses that have been well tolerated by patients. Recent non-clinical experiments that explored the effects of vorinostat in combination with other chemotherapeutic agents have begun to illuminate potential mechanisms of action for this histone deacetylase inhibitor and are providing guidance for new avenues of clinical investigation.
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43
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Nolan L, Johnson PWM, Ganesan A, Packham G, Crabb SJ. Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential? Br J Cancer 2008; 99:689-94. [PMID: 18728657 PMCID: PMC2528143 DOI: 10.1038/sj.bjc.6604557] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Histone deacetylase inhibitors have progressed rapidly from the laboratory to clinical testing. This review highlights the promising data for their combination with a wide range of established and novel anticancer agents and discusses the mechanisms that underpin these interactions.
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Affiliation(s)
- L Nolan
- Cancer Research UK Clinical Centre, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK
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44
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Hu ZZ, Huang H, Cheema A, Jung M, Dritschilo A, Wu CH. Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data. ACTA ACUST UNITED AC 2008; 1:47-60. [PMID: 19088860 DOI: 10.4172/jpb.1000009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Functional analysis and interpretation of large-scale proteomics and gene expression data require effective use of bioinformatics tools and public knowledge resources coupled with expert-guided examination. An integrated bioinformatics approach was used to analyze cellular pathways in response to ionizing radiation. ATM, or ataxia-telangiectasia mutated , a serine-threonine protein kinase, plays critical roles in radiation responses, including cell cycle arrest and DNA repair. We analyzed radiation responsive pathways based on 2D-gel/MS proteomics and microarray gene expression data from fibroblasts expressing wild type or mutant ATM gene. The analysis showed that metabolism was significantly affected by radiation in an ATM dependent manner. In particular, purine metabolic pathways were differentially changed in the two cell lines. The expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2) was increased in ATM-wild type cells at both mRNA and protein levels, but no changes were detected in ATM-mutated cells. Increased expression of p53 was observed 30min after irradiation of the ATM-wild type cells. These results suggest that RRM2 is a downstream target of the ATM-p53 pathway that mediates radiation-induced DNA repair. We demonstrated that the integrated bioinformatics approach facilitated pathway analysis, hypothesis generation and target gene/protein identification.
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Affiliation(s)
- Zhang-Zhi Hu
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20007, USA
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45
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Rimkus SA, Katzenberger RJ, Trinh AT, Dodson GE, Tibbetts RS, Wassarman DA. Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia. Genes Dev 2008; 22:1205-20. [PMID: 18408079 DOI: 10.1101/gad.1639608] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mutations in ATM (Ataxia telangiectasia mutated) result in Ataxia telangiectasia (A-T), a disorder characterized by progressive neurodegeneration. Despite advances in understanding how ATM signals cell cycle arrest, DNA repair, and apoptosis in response to DNA damage, it remains unclear why loss of ATM causes degeneration of post-mitotic neurons and why the neurological phenotype of ATM-null individuals varies in severity. To address these issues, we generated a Drosophila model of A-T. RNAi knockdown of ATM in the eye caused progressive degeneration of adult neurons in the absence of exogenously induced DNA damage. Heterozygous mutations in select genes modified the neurodegeneration phenotype, suggesting that genetic background underlies variable neurodegeneration in A-T. The neuroprotective activity of ATM may be negatively regulated by deacetylation since mutations in a protein deacetylase gene, RPD3, suppressed neurodegeneration, and a human homolog of RPD3, histone deacetylase 2, bound ATM and abrogated ATM activation in cell culture. Moreover, knockdown of ATM in post-mitotic neurons caused cell cycle re-entry, and heterozygous mutations in the cell cycle activator gene String/CDC25 inhibited cell cycle re-entry and neurodegeneration. Thus, we hypothesize that ATM performs a cell cycle checkpoint function to protect post-mitotic neurons from degeneration and that cell cycle re-entry causes neurodegeneration in A-T.
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Affiliation(s)
- Stacey A Rimkus
- Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA
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Le Deist F, Fischer A. Primary T-cell immunodeficiencies. Clin Immunol 2008. [DOI: 10.1016/b978-0-323-04404-2.10035-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Lee JS. Activation of ATM-dependent DNA damage signal pathway by a histone deacetylase inhibitor, trichostatin A. Cancer Res Treat 2007; 39:125-30. [PMID: 19746219 DOI: 10.4143/crt.2007.39.3.125] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Accepted: 09/08/2007] [Indexed: 11/21/2022] Open
Abstract
PURPOSE Ataxia-telangiectasia mutated (ATM) kinase regulates diverse cellular DNA damage responses, including genome surveillance, cell growth, and gene expression. While the role of histone acetylation/deacetylation in gene expression is well established, little is known as to whether this modification can activate an ATM-dependent signal pathway, and whether this modification can thereby be implicated in an ATM-mediated DNA damage response. MATERIALS AND METHODS Formation of H2AXgamma foci was examined in HeLa and U(2)OS cells following treatment with a histone deacetylase inhibitor, Trichostatin A (TSA). We determine an ATM-dependency of the TSA-induced DNA damage signal pathway using isogenic A-T (ATM(-)) and control (ATM(+)) cells. We monitored the phosphorylation of ATM, an ATM-downstream effector kinase, Chk2, and H2AXgamma to detect the activation of the ATM-dependent DNA damage signal pathway. RESULTS Exposure of cells to TSA results in the formation of H2AXgamma foci in HeLa and U(2)OS cells. The TSA-induced formation of H2AXgamma foci occurs in an ATM-dependent manner. TSA induces phosphorylation of serine 1981 of ATM, accumulation of phosphorylated H2AX and Chk2, and formation of H2AX foci, in a manner analogous to genotoxic DNA damage. CONCLUSION In this work, we show that TSA induces a DNA damage signaling pathway in an ATM-dependent manner. These results suggest that ATM can respond to altered histone acetylation induced by the histone deacetylase inhibitor, TSA.
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Affiliation(s)
- Jong-Soo Lee
- Department of Biological Sciences, College of Natural Sciences and Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
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Zhang Y, Carr T, Dimtchev A, Zaer N, Dritschilo A, Jung M. Attenuated DNA damage repair by trichostatin A through BRCA1 suppression. Radiat Res 2007; 168:115-24. [PMID: 17722998 DOI: 10.1667/rr0811.1] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2006] [Accepted: 02/19/2007] [Indexed: 11/03/2022]
Abstract
Recent studies have demonstrated that some histone deacetylase (HDAC) inhibitors enhance cellular radiation sensitivity. However, the underlying mechanism for such a radiosensitizing effect remains unexplored. Here we show evidence that treatment with the HDAC inhibitor trichostatin A (TSA) impairs radiation-induced repair of DNA damage. The effect of TSA on the kinetics of DNA damage repair was measured by performing the comet assay and gamma-H2AX focus analysis in radioresistant human squamous carcinoma cells (SQ-20B). TSA exposure increased the amount of radiation-induced DNA damage and slowed the repair kinetics. Gene expression profiling also revealed that a majority of the genes that control cell cycle, DNA replication and damage repair processes were down-regulated after TSA exposure, including BRCA1. The involvement of BRCA1 was further demonstrated by expressing ectopic wild-type BRCA1 in a BRCA1 null cell line (HCC-1937). TSA treatment enhanced radiation sensitivity of HCC-1937/wtBRCA1 clonal cells, which restored cellular radiosensitivity (D(0) = 1.63 Gy), to the control level (D(0) = 1.03 Gy). However, TSA had no effect on the level of radiosensitivity of BRCA1 null cells. Our data demonstrate for the first time that TSA treatment modulates the radiation-induced DNA damage repair process, in part by suppressing BRCA1 gene expression, suggesting that BRCA1 is one of molecular targets of TSA.
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Affiliation(s)
- Yin Zhang
- Division of Radiation Research, Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
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Camphausen K, Tofilon PJ. Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization. J Clin Oncol 2007; 25:4051-6. [PMID: 17827453 DOI: 10.1200/jco.2007.11.6202] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Recently, strategies to enhance tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. A molecular target that has begun to receive considerable attention is histone acetylation. Histone acetylation is determined by the dynamic interaction of two families of enzymes: histone acetylases and histone deacetylases (HDACs). Histone acetylation plays a role in regulating chromatin structure and gene expression—two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity. This has led to the generation of a relatively large number of structurally diverse compounds that can inhibit HDAC activity resulting in histone hyperacetylation. Many of the newer HDAC inhibitor compounds have been designed with better bioavailability or pharmacology than the first-generation compounds. Whereas a number of these second-generation HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, early clinical data demonstrate only cytostasis when used as monotherapy. However, recent preclinical studies have indicated that HDAC inhibitors from structurally diverse classes can enhance both the in vitro and in vivo radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. HDAC inhibitors are in clinical trials as single modalities, in combination with chemotherapeutic agents, and recently, in combination with radiotherapy.
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Affiliation(s)
- Kevin Camphausen
- Radiation Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
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Zhang P, Dilley C, Mattson MP. DNA damage responses in neural cells: Focus on the telomere. Neuroscience 2007; 145:1439-48. [PMID: 17207936 PMCID: PMC1924472 DOI: 10.1016/j.neuroscience.2006.11.052] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2006] [Revised: 11/20/2006] [Accepted: 11/22/2006] [Indexed: 01/24/2023]
Abstract
Postmitotic neurons must survive for the entire life of the organism and be able to respond adaptively to adverse conditions of oxidative and genotoxic stress. Unrepaired DNA damage can trigger apoptosis of neurons which is typically mediated by the ataxia telangiectasia mutated (ATM)-p53 pathway. As in all mammalian cells, telomeres in neurons consist of TTAGGG DNA repeats and several associated proteins that form a nucleoprotein complex that prevents chromosome ends from being recognized as double strand breaks. Proteins that stabilize telomeres include TRF1 and TRF2, and proteins known to play important roles in DNA damage responses and DNA repair including ATM, Werner and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). We have been performing studies of developing and adult neurons aimed at understanding the effects of global and telomere-directed DNA damage responses in neuronal plasticity and survival in the contexts of aging and neurodegenerative disorders. Deficits in specific DNA repair proteins, including DNA-PKcs and uracil DNA glycosylase (UDG), render neurons vulnerable to adverse conditions of relevance to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease and stroke. Similarly, early postmitotic neurons with reduced telomerase activity exhibit accentuated responses to DNA damage and are prone to apoptosis demonstrating a pivotal role for telomere maintenance in both mitotic cells and postmitotic neurons. Our recent findings suggest key roles for TRF2 in regulating the differentiation and survival of neurons. TRF2 affects cell survival and differentiation by modulating DNA damage pathways, and gene expression. A better understanding of the molecular mechanisms by which neurons respond to global and telomere-specific DNA damage may reveal novel strategies for prevention and treatment of neurodegenerative disorders. Indeed, work in this and other laboratories has shown that dietary folic acid can protect neurons against Alzheimer's disease by keeping homocysteine levels low and thereby minimizing the misincorporation of uracil into DNA in neurons.
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Affiliation(s)
- P Zhang
- Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA
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