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Targeting Epigenetic Regulators for Cancer Therapy: Mechanisms and Advances in Clinical Trials Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials Yuan Cheng1, Cai He1, Manni Wang1, Xuelei Ma1, Fei Mo1, Shengyong Yang1, Junhong Han1 and Xiawei Wei1 Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes. Signal Transduction and Targeted Therapy (2019) ;4:62 https://doi.org/10.1038/s41392-019-0095-0 INTRODUCTION biological processes, the epigenome cooperates with other 1234567890();,: After the discovery of DNA and the double helix structure, classic regulatory factors, such as transcription factors and noncoding genetics has long assumed that the sequences of DNA determine RNAs, to regulate the expression or repression of the genome. the phenotypes of cells. DNA is packaged as chromatin in cells, Epigenetics can also be influenced by cellular signaling pathways with nucleosomes being the fundamental repeating unit. Four and extracellular stimuli. These effects are temporary and yet long- core histones (H2A, H2B, H3, and H4) form an octamer and are standing. Given the importance of epigenetics in influencing cell then surrounded by a 147-base-pair (bp) segment of DNA. functions, a better understanding of both normal and abnormal Nucleosomes are separated by 10–60 bp DNA. Researchers have epigenetic processes can help to understand the development gradually found organisms that share the same genetic informa- and potential treatment of different types of diseases, including tion but have different phenotypes, such as somatic cells from the cancer. same individual that share a genome but function completely The etiology of cancer is quite complicated and involves both differently. The term epigenetics was first proposed and environmental and hereditary influences. In cancer cells, the established in 1942 when Conrad Waddington tried to interpret alteration of genomic information is usually detectable. Like the connection between genotype and phenotype.1 Later, Arthur genome instability and mutation, epigenome dysregulation is also Riggs and his group interpreted epigenetics as inherited pervasive in cancer (Fig. 2). Some of the alterations determine cell differences in mitosis and meiosis, which could explain the function and are involved in oncogenic transformation.4 However, changes in phenotypes. They were both trying to find the link by reversing these mutations by drugs or gene therapy, the between genotype and phenotype. Epigenetics is usually referred phenotype of cancer can revert to normal. Holliday proposed a to as a genomic mechanism that reversibly influences gene theory that epigenetic changes are responsible for tumorigenesis. expression without altering DNA sequences. Holliday assumed The alteration of cellular methylation status by a specific that epigenetics was also mitotically and/or meiotically heritable methyltransferase might explain the differences in the probability without DNA sequence change. Aberrant DNA methylation could of malignant transformation.5 In clinical settings, we noticed that be repaired via meiosis, but some patterns are still transmitted to although cancer patients share the same staging and grade, they offspring.2 This phenomenon covers a wide range of cellular present totally different outcomes. In tumor tissues, different activities, such as cell growth, differentiation, and disease tumor cells show various patterns of histone modification, development, and is heritable.3 Generally, epigenetic events genome-wide or in individual genes, indicating that epigenetic involve DNA methylation, histone modification, the readout of heterogeneity exists at a cellular level.6 Likewise, using molecular these modifications, chromatin remodeling and the effects of biomarkers is thought to be a potential method to divide patients noncoding RNA. The elements involved in different modification into different groups. It is important to note that tumorigenesis is patterns can be divided into three roles, “writer,”“reader,” and the consequence of the combined action of multiple epigenetic “eraser”. The “writers” and “erasers” refer to enzymes that transfer events. For example, the repression of tumor suppressor genes is or remove chemical groups to or from DNA or histones, usually caused by methylation of DNA CpG islands together with respectively. “Readers” are proteins that can recognize the hypoacetylated and hypermethylated histones.7 During gene modified DNA or histones (Fig. 1). To coordinate multiple silencing, several hallmarks of epigenetic events have been 1Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China Correspondence: Xiawei Wei ([email protected]) These authors contributed equally: Yuan Cheng, Cai He Received: 14 July 2019 Revised: 16 October 2019 Accepted: 24 October 2019 © The Author(s) 2019 Targeting epigenetic regulators for cancer therapy: mechanisms and. Cheng et al. 2 Fig. 1 Epigenetic regulation of DNA methylation, histone acetylation, and histone methylation. Gene silencing in mammalian cells is usually caused by methylation of DNA CpG islands together with hypoacetylated and hypermethylated histones. The “writers” (DNMTs, HATs, and HMTs) and “erasers” (DNA-demethylating enzymes, HDACs, and KDMs) are enzymes responsible for transferring or removing chemical groups to or from DNA or histones; MBDs and other binding proteins are “readers” that recognize methyl-CpGs and modified histones. DNMTs, DNA methyltransferases; MBDs, methyl-CpG binding domain proteins; HATs, histone acetylases; HDACs, histone deacetylases; HMTs, histone methyltransferases; KDMs, histone-demethylating enzymes. identified, including histone H3 and H4 hypoacetylation, histone transcription or repressing gene transcription and affecting H3K9 methylation, and cytosine methylation.8,9 chromatin stability.18 Therefore, epigenetics enables us to investigate the potential The precise mechanism by which DNA methylation affects mechanism underlying cancer phenotypes and provides poten- chromatin structure unclear, but it is known that methyl-DNA is tial therapy options. In this review, we focused and briefly closely associated with a closed chromatin structure, which is expanded on three aspects of epigenetics in cancer: DNA relatively inactive.19 Hypermethylation of promoters and hypo- methylation, histone acetylation and histone methylation. methylation of global DNA are quite common in cancer. It is Finally, we summarized the current developments in epigenetic widely accepted that gene promoters, especially key tumor therapy for cancers. suppressor genes, are unmethylated in normal tissues and highly methylated in cancer tissues.20 P16, a tumor suppressor encoded by CDKN2A, has been found to gain de novo methylation in ~20% DNA METHYLATION of different primary neoplasms.21 Mutations in important and well- The DNA methylation pattern in mammals follows certain rules. studied tumor-suppressive genes, such as P53 and BRCA1, are Germ cells usually go through a stepwise demethylation to ensure frequently identified in multiple cancers.22–24 Studies have found global repression and suitable gene regulation during embryonic that the level of methylation is positively associated with tumor development. After implantation, almost all CpGs experience de size. In support of this, a whole-genome methylation array analysis novo methylation except for those that are protected.10 Normal in breast cancer patients found significantly increased CpG dynamic changes in DNA methylation and demethylation based methylation in FES, P2RX7, HSD17B12, and GSTM2 coincident on altered expression of enzymes have been known to be with increasing tumor stage and size.25 After analysis of long- associated with aging.11,12 However, inappropriate methylation of range epigenetic silencing at chromosome 2q14.2, methylation of DNA can result in multiple diseases, including inflammatory EN1 and SCTR, the first well-studied example of coordinated diseases, precancerous lesions, and cancer.13–15 Of note, de novo epigenetic modification, was significantly increased in colorectal methylation of DNA in cancer serves to prevent reactivation of and prostate cancers.26,27 EN1 methylation has also been repressed genes rather than inducing gene repression.16 Because observed to be elevated by up to 60% in human salivary gland researchers have found that over 90% of genes undergoing de adenoid cystic carcinoma.28 Of note, only ~1% of normal samples novo methylation in cancer are already in a repressed status in exhibited EN1 CpG island hypermethylation.26 Therefore, the normal cells.17 Nevertheless, aberrant DNA methylation is thought significant difference between cancer cells and normal cells makes to serve as a hallmark
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