Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
20
1-2
2015
Preface: Histone Deacetylases as Therapeutic Targets
v-vi
10.1615/CritRevOncog.2015013241
Paola
Perego
Molecular Pharmacology Unit, Department of Applied Research and Technological Development,
Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42/via Venezian 1, 20133 Milan, Italy
Deacetylation of Chromatin and Gene Expression Regulation: A New Target for Epigenetic Therapy
1-17
10.1615/CritRevOncog.2014012463
Heidi
Olzscha
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford, OX3 7DQ, UK
Semira
Sheikh
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford, OX3 7DQ, UK
Nicholas B.
La Thangue
Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Old Road Campus, off Roosevelt Drive, Oxford, OX3 7DQ, UK
epigenetics
chromatin
acetylation
histone deacetylase
cancer
HDAC inhibitor
cell death
biomarker
Besides the genetic information thath is encoded by DNA, heritable information can also be passed on without relying on changes in the nucleotide sequence of DNA, a phenomenon known as epigenetics. Gene expression in eukaryotes is partly regulated by epigenetic mechanisms both at the DNA and histone protein levels. Chromatin structure can be influenced by various modifications, including the reversible posttranslational processes of acetylation and deacetylation of DNA-binding proteins. Histone acetyl transferase (HAT) is referred to as the writer of this process, whereas histone deacetylase (HDAC) is the eraser of this lysine modification. Dysregulation of gene expression and changes in the HDAC expression profile have been associated with carcinogenesis, and HDAC inhibitors are already approved for the treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma. These inhibitors are able to influence epigenetic processes by targeting HDAC activity, increasing nuclear histone acetylation status, and contributing to chromatin remodeling, thereby affecting gene expression. In addition, HDACs also act on a plethora of cytosolic proteins with many cellular functions, including angiogenesis, immune responses, and autophagy. In this review, we will give an overview of histone deacetylase and how it can regulate gene expression at the chromatin level.
Altered Expression of Histone Deacetylases in Cancer
19-34
10.1615/CritRevOncog.2014012554
Diana
Montezuma
Department of Pathology, Cancer Biology & Epigenetics Group, Research Center, Portuguese Oncology Institute-Porto (Cl-IPO-Porto), Rua Dr. Antonio Bernardino Almeida, 4200-072, Porto, Portugal
Rui Manuel Ferreira
Henrique
Department of Pathology, Portuguese Oncology Institute—Porto; and Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Sa-lazar (ICBAS), University of Porto, Portugal
Carmen
Jeronimo
Cancer Biology & Epigenetics Group, Research Center, Portuguese Oncology Institute-Porto (Cl-IPO-Porto), Rua Dr. Antonio Bernardino Almeida, 4200-072, Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences
histone deacetylases
cancer
genitourinary
bladder
prostate
Epigenetic mechanisms, including histone deacetylation, are commonly deregulated in cancer. Histone deacetylases (HDACs) play an important role in tumorigenesis and their value as therapeutic targets has been under intense investigation in recent years. In addition to classical HDACs (HDAC classes I, II, and IV), sirtuins (class III HDACs) are currently in the spotlight of cancer research showing promise as cancer biomarkers and therapeutic targets. Translating research knowledge into the clinical setting is, however, a challenging and demanding task. This review describes the association between HDAC deregulation and cancer promotion and highlights recent advances in the use of HDAC inhibitors in the management of neoplastic diseases, with emphasis on urological tumors. Sirtuins' bivalent role in tumor development and therapeutic agents targeting these molecules will be also addressed.
Histone Deacetylases and Mechanisms of Regulation of Gene Expression
35-47
10.1615/CritRevOncog.2015012997
Hong Ping
Chen
Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, RI; Department of Histology and Embryology, Medical College, Nanchang University, Nanchang, China
Yu Tina
Zhao
Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, RI
Ting C.
Zhao
Department of Surgery, Boston University Medical School, Boston University, Roger Williams Medical Center, Providence, RI
histone deacetylase
histone acetylation
cancer
drug target
In recent years it has become widely recognized that histone modification plays a pivotal role in controlling gene expression and is involved in a wide spectrum of disease regulation. Histone acetylation is a major modification that affects gene transcription and is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs acetylate lysines of histone proteins, resulting in the relaxation of chromatin structure, and they also facilitate gene activation. Conversely, HDACs remove acetyl groups from hyperacetylated histones and suppress general gene transcription. In addition to histones, numerous nonhistone proteins can be acetylated and deacetylated, and they also are involved in the regulation of a wide range of diseases. To date there are 18 HDACs in mammals classified into 4 classes based on homology to yeast HDACs. Accumulating evidence has revealed that HDACs play crucial roles in a variety of biological processes including inflammation, cell proliferation, apoptosis, and carcinogenesis. In this review we summarize the current state of knowledge of HDACs in carcinogenesis and describe the involvement of HDACs in cancer-associated molecular processes. It is hoped than an understanding of the role of HDACs in cancer will lead to the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease.
Multifaceted Modulation of SIRT1 in Cancer and Inflammation
49-64
10.1615/CritRevOncog.2014012374
Hui
Yang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Yujing
Bi
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing China
Lixiang
Xue
Department of Biochemistry and Molecular Biology, Peking University, Health Science Center, Beijing China
Jian
Wang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Yun
Lu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Zhengguo
Zhang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Xi
Chen
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Yiwei
Chu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
Ruifu
Yang
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing China
Ruoning
Wang
Center for Childhood Cancer & Blood Diseases, The Research Institute at Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA
Guangwei
Liu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai China; Biotherapy Research Center, Institute of Immunobiology, Fudan University
SIRT1
deacetylase
cancer
metabolism
inflammation
immune cell
tolerance
immunoregulation
SIRT1 is a highly conserved NAD+-dependent protein deacetylase that is involved in diverse cellular processes. SIRT1 can deacetylate not only histones, but also a growing number of nonhistone substrates involved in multiple signaling pathways. Accumulating evidence has indicated that SIRT1 is a key regulator of life span extension, DNA damage, metabolism stress, inflammation, and cancer. In inflammation, SIRT1 deacetylates several transcription factors and regulates the immune cell responses. In cancer, recent discoveries revealed opposite effects of SIRT1 as an oncoprotein or a tumor suppressor under different conditions. In the tumor microenvironment, both infiltrated immune cells and cancer cells can be affected by SIRT1. Understanding the proper cancer-related functions of SIRT1 in both systems may provide potential evidence for SIRT1-based therapies. Here, we discuss the current understanding of SIRT1 in regulating immune responses and tumorigenesis.
HDAC6-Dependent Functions in Tumor Cells: Crossroad with the MAPK Pathways
65-81
10.1615/CritRevOncog.2014012484
Joshua
Haakenson
University of South Florida, Tampa, FL
Jheng-Yu
Wu
University of South Florida, Tampa, FL
Shengyan
Xiang
University of South Florida, Tampa, FL
Kendra A.
Williams
University of South Florida, Tampa, FL
Wenlong
Bai
University of South Florida, Tampa, FL; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Xiaohong
Zhang
University of South Florida, Tampa, FL; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
HDACs
kinase
MAPK
acetylation
phosphorylation
Histone deacetylase 6 (HDAC6) is emerging as a novel therapeutic target in cancer treatment. HDAC6 plays an important role in cell migration, cell transformation, and DNA damage response. Our and others' studies have linked HDAC6's functions and HDAC6's regulation to the mitogen-activated protein kinase (MAPK) pathways. In particular, HDAC6's activity has been found to be regulated by EGF-EGFR-Ras-Raf-MEK-ERK signaling. Inversely, HDAC6 has been reported to modulate the functions of EGFR and Ras. In this review, we summarize the literature on HDAC6 and MAPK pathways, and emphasize the interaction between HDAC6 and the ERK-MAPK signaling cascade.
Drug Combinations with HDAC Inhibitors in Antitumor Therapy
83-117
10.1615/CritRevOncog.2014012378
Noemi
Arrighetti
Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Cristina
Corno
Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Laura
Gatti
Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS
Istituto Nazionale dei Tumori, Milano, Italy
HDAC inhibitors
drug combination
antitumor therapy
The treatment of tumor cells with HDAC inhibitors (HDACi) induces a range of effects including apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune response, and altered angiogenesis. The single-agent activities of several HDACi have been tested in preclinical and clinical studies and are currently the subject of ongoing clinical trials. Although HDACi have been shown to be effective as a single agent against a defined subset of hematological tumors, less convincing results have been found in the treatment of solid tumors. Since current clinical trials of single-agent HDACi showed limited efficacy, in this review we focus on drug combinations including HDACi with conventional chemotherapeutic agents and novel targeted agents. Particular emphasis has been devoted to combinations effective in solid tumors and to combinations between HDACi and immunotherapies. An outline of novel combination strategies, including a new generation of more potent and specific HDACi (e.g., compounds with adamantine and noradamantane as scaffolds) as well as chemical hybrid molecules, has been provided. The paradoxical role of HDACs as tumor suppressors in developing tumors and as therapeutic targets in established neoplasms has also been considered.
Histone Deacetylases and Cancer-Associated Angiogenesis: Current Understanding of the Biology and Clinical Perspectives
119-137
10.1615/CritRevOncog.2014012423
Andrei
Turtoi
Metastasis Research Laboratory, GIGA Cancer, University of Liege, 4000 Liege, Belgium
Paul
Peixoto
Metastasis Research Laboratory, GIGA Cancer, University of Liege, 4000 Liege, Belgium
Vincent
Castronovo
Metastasis Research Laboratory, GIGA Cancer, University of Liege, 4000 Liege, Belgium
Akeila
Bellahcene
Metastasis Research Laboratory, GIGA Cancer, University of Liege, 4000 Liege, Belgium
HDAC
preclinical
sirtuins
inhibitors
Histone deacetylase enzymes (HDACs) have been shown to be important to the development and progression of human cancers. Angiogenesis is a vital process that facilitates tumor growth and survival. More than a dozen of different activators and inhibitors are involved in at least as many diverse mechanisms to control angiogenesis. HDACs directly or indirectly control many of these regulators. In the current review, we give a brief overview of molecular mechanisms of HDAC actions and link these to the current knowledge concerning HDAC-mediated regulation of tumor-associated angiogenesis. HDAC specific knockdown studies and the use of pan-HDAC inhibitors (HDACi) contributed to the identification of: (i) HDACs that are key to angiogenesis and (ii) their multiple protein targets essential for angiogenic process. The clinical development of HDACi is an active area of investigation. In the scope of this review, we highlight several preclinical studies that examine the anti-angiogenic role of HDACi. Certainly, there is still much to be learned about the use of HDACi to inhibit tumoral angiogenesis. Recent efforts in the clinics aiming to combine broad HDACi (mainly vorinostat, which is FDA approved for T-cell lymphoma) with other anti-angiogenic therapies could, however, bring the proof that the lack of specificity of pan-HDACi may not be a major issue as compared with (long-time idealized) selective inhibitors targeting one particular HDAC.
Modulation of Immune Responses by Histone Deacetylase Inhibitors
139-154
10.1615/CritRevOncog.2014012393
Sonja
Schotterl
Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, University of Tubingen, Tubingen, Germany
Heiko
Brennenstuhl
Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, University of Tubingen, Tubingen, Germany
Ulrike
Naumann
Hertie Institute for Clinical Brain Research and Center Neurology, Department of Vascular Neurology, Laboratory of Molecular Neuro-Oncology, University of Tubingen, Tubingen, Germany
histone deacetylase inhibition
immune modulation
cancer
autoimmune disease
graft versus host disease
persistent virus infection
Recent studies have demonstrated that histone deacetylase (HDAC) inhibitors (HDACi) have potential immunomodulatory activity since they affect the immune surveillance by regulating the production of cytokines, alter the activity and function of macrophages and dendritic cells (DC), regulate the transcription of a variety of immune-stimulating genes, and can modulate the activity of immune effector cells of both the innate and adaptive immune system. Besides their immunostimulatory activity, HDACi can induce growth arrest and cell death, and modulate a subset of cellular functions such as cell motility or differentiation. This makes HDACi interesting therapeutic candidates for the treatment of a variety of human diseases like cancer, autoimmune, and graft versus host diseases. Besides these, HDACs have been shown to be involved in virus replication and pathogenesis, and it was recently shown that HDACi provide therapeutic effects in the treatment of oncogenic virus infections and associated malignancies. This review will further give information about the different families of HDACs and their opponents, the histone acetylases (HATs), about the classes and function of specific HDACi, and their use in the treatment of human diseases.