Ismail et al. Epigenetics & Chromatin (2018) 11:33 https://doi.org/10.1186/s13072-018-0203-3 Epigenetics & Chromatin REVIEW Open Access KDM1A microenvironment, its oncogenic potential, and therapeutic signifcance Tayaba Ismail1, Hyun‑Kyung Lee1, Chowon Kim1, Taejoon Kwon2, Tae Joo Park2* and Hyun‑Shik Lee1* Abstract The lysine-specifc histone demethylase 1A (KDM1A) was the frst demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a favin adenine dinucleotide (FAD)-dependent amine oxidase domain, demethylates histone 3 lysine 4 and histone 3 lysine 9 (H3K4me1/2 and H3K9me1/2). It has emerged as an epigenetic developmental regulator and was shown to be involved in carcinogenesis. The functional diversity of KDM1A originates from its complex structure and interactions with transcription factors, promoters, enhancers, onco‑ proteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenviron‑ ment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifer that regulates the growth and diferentiation potential of cells. A detailed analysis of the mechanisms underlying the interactions between KDM1A and the associated complexes will help to improve our understanding of epigenetic regulation, which may enable the discovery of more efective anticancer drugs. Keywords: Histone demethylation, Carcinogenesis, Acute myeloid leukemia, KDM1A, TLL Background X-chromosome, that are involved in the regulation of Epigenetic modifcations are crucial for physiological development. Additionally, these alterations may repre- development and steady-state gene expression in eukary- sent aberrant markers indicating the development of dif- otes [1] and are required for various biological processes ferent types of cancer and other diseases [5–7]. ranging from gene expression to disease pathogenesis Lysine residues can be mono-, di-, and tri-methylated [2]. DNA methylation, histone modifcations, and post- in the nucleosome at strategic chromatin positions, and translational modifcations (PTMs) represent epigenetic these methylated states have diferent functions [8]. alterations that may, alone or in combination, modify Lysine no. 4, 9, 27, 36, and 79 of histone H3 and lysine chromatin structure and gene activity by facilitating 20 of histone H4 are the most frequently studied histone either gene activation or repression depending on the methylation sites and are associated with various biologi- regulator type [3]. Histone methylation is the most versa- cally signifcant processes [9]. Tese methylation marks tile epigenetic modifcation involved in the establishment were considered stable and irreversible prior to the dis- and maintenance of the epigenome [4]. Te methylation covery of the molecules termed “erasers,” i.e., histone of lysine residues at specifc chromatin positions is essen- demethylases [10]. Shi et al. made the frst discovery of tial for many processes, such as the activation and repres- histone lysine demethylase in 2004 [11], and this led to sion of transcription, transcriptional silencing mediated the establishment of new paradigms in the feld of epi- by heterochromatin, DNA repair, and inactivation of the genetics (Fig. 1). Tese epigenetic regulators have been clustered into two subclasses [12]: one, including the majority of these regulators, containing a jumonji domain *Correspondence: [email protected]; [email protected] 1 KNU‑Center for Nonlinear Dynamics, CMRI, School of Life Sciences, that depend on iron and oxoglutarate as cofactors [13], BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, and the other comprising of two lysine-specifc demethy- Kyungpook National University, Daegu 41566, South Korea lases that contain an amine oxidase domain and rely on 2 School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, South Korea favin adenine dinucleotide (FAD) as their cofactor [14]. © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ismail et al. Epigenetics & Chromatin (2018) 11:33 Page 2 of 15 structure, which is involved in the maintenance of its EPIGENETIC MODIFICATIONS microenvironment by establishing complex interactions with a variety of transcriptional factors, promoters, acti- vators, corepressors, and noncoding RNAs. Additionally, DNA Histone we discuss the versatile nature of KDM1A as an epige- Micro RNAs Methylaon Modificaons netic modifer, regulating the expression of a number of genes involved in epithelial–mesenchymal transition (EMT). Moreover, the potential and challenges associ- ated with KDM1A therapeutic targeting are summarized KDMs, HDACs, HMTs, HATs, Bromo, chromo, here, together with a brief description of the similarities Phosphatases Kinases & Tudor proteins and diferences between this demethylase and its recently Biological Significance discovered homolog, KDM1B, the other member of the FAD-dependent demethylase family. Structural analysis of KDM1A Cell Cycle, Replicaon, Transcripon, Apoptosis, Pluripotency, DNA Repair KDM1A, the frst demethylase to be identifed, is also known as LSD1, AOF2, BHC110, or KIAA0601 [21], and Developmental Disorders & Carcinogenesis structural analyses have demonstrated that this protein Fig. 1 Epigenetic modifcations and their biological roles. contains an amine oxidase-like domain (AOL) [22]. Ini- Epigenetic modifcations are highly dynamic, and diferent types of modifcations have been identifed: DNA methylation, histone tially, KDM1A was considered a nuclear protein, similar modifcations, and microRNA‑mediated modifcations. Histone to the FAD-dependent amine oxidases, but it was later modifcations are extremely versatile, and proteins known as “writers,” shown to be a demethylase [23]. Despite the structural “readers,” and “erasers” are involved in this process. The writers, such similarity between the AOL domain of KDM1A and as histone methyltransferases (HMTs), histone acetyltransferases the amine oxidase domains of other amine oxidases, it (HATs), and kinases, add specifc marks on sequences of amino acids on histone tails. Readers, such as proteins containing a exhibits numerous diferences, e.g., it contains a SWIRM bromo‑domain, chromo‑domain, or tudor‑domain, are able to read (swi3p/Rsc8p/Moira) domain at its N-terminus, which these specifc marks, which are further removed by the erasers, plays a signifcant role in protein–protein interactions i.e., histone demethylases (KDMs), histone deacetylases (HDACs), [24]. Furthermore, KDM1A contains a TOWER domain and phosphatases. These histone modifers, together with other (90-residue insert), dividing the AOL domain into two epigenetic regulators, play an important role in the regulation of diverse biological functions [7] subdomains (Fig. 2) [25, 26]. One subdomain of AOL interacts with the SWIRM domain, forming a core struc- ture that binds FAD, while the other specifcally binds the substrate [27]. Te FAD-binding subdomain of AOL All histone modifers were shown to have important is similar to the amine oxidase domain of other amine roles in gene regulation and epigenome establishment oxidases, but the substrate-binding subdomain contains [15]. However, lysine-specifc histone demethylase 1A a large binding pocket with acidic features at its surface (KDM1A/LSD1), being the frst identifed histone dem- to facilitate the accommodation of long basic histone ethylase, has been widely explored, and numerous studies tails by maintaining specifc interactions with the frst 20 have described its biological roles [16]. KDM1A repre- amino acids of histone 3 (H3) [28]. Moreover, the active sents an important enzyme that plays signifcant roles in site of KDM1A possesses side chains at its rim that are the regulation of embryonic development and diferen- negatively charged in order to establish interactions with tiation [17]. Furthermore, together with associated pro- the tail of the histone substrate through hydrogen bond- teins, this protein regulates many physiological processes ing and salt bridges [29]. Tis unique KDM1A binding involved in the shape and identity determination of stem site mediates its demethylation function and enables and progenitor cells and also plays a role in their diferen- KDM1A to recognize a wide range of nonhistone sub- tiation into specialized cells, i.e., hematopoietic, neural, strates [30–32]. mesenchymal, sperm, and fat cells [18, 19]. KDM1A has Te SWIRM domain of KDM1A does not bind with also been associated with the development of a variety of DNA molecules, as it is specifc for protein–protein pathological conditions, such as cancer, neuronal disor- interactions and maintains the structural integrity of ders, and viral infections [20]. protein substrates [24, 27]. Furthermore, it is involved in Te functional diversity of KDM1A is supported by its altering the substrate specifcity of KDM1A from H3K4 complex structure