KDM1A microenvironment, its oncogenic potential, and therapeutic significance

Abstract

The lysine-specific histone demethylase 1A (KDM1A) was the first demethylase to challenge the concept of the irreversible nature of methylation marks. KDM1A, containing a flavin 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, oncoproteins, and tumor-associated genes (tumor suppressors and activators). In this review, we discuss the microenvironment of KDM1A in cancer progression that enables this protein to activate or repress target gene expression, thus making it an important epigenetic modifier that regulates the growth and differentiation 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 effective anticancer drugs.

Keywords: Acute myeloid leukemia; Carcinogenesis; Histone demethylation; KDM1A; TLL.

Fig. 1

Epigenetic modifications and their biological roles. Epigenetic modifications are highly dynamic, and different types of modifications have been identified: DNA methylation, histone modifications, and microRNA-mediated modifications. Histone modifications are extremely versatile, and proteins known as “writers,” “readers,” and “erasers” are involved in this process. The writers, such as histone methyltransferases (HMTs), histone acetyltransferases (HATs), and kinases, add specific marks on sequences of amino acids on histone tails. Readers, such as proteins containing a bromo-domain, chromo-domain, or tudor-domain, are able to read these specific marks, which are further removed by the erasers, i.e., histone demethylases (KDMs), histone deacetylases (HDACs), and phosphatases. These histone modifiers, together with other epigenetic regulators, play an important role in the regulation of diverse biological functions [7]

Fig. 2

Structural domain analysis of KDM1A and KDM1B. Lysine-specific demethylase 1A and 1B each contain an amine oxidase-like domain and a SWIRM (SWI3, RSC8, and Moira) domain. The SWIRM domain of KDM1A is specific for chromatin–protein interactions, while that of KDM1B interacts with glyoxylate reductase 1 (GLYR1). KDM1A and 1B are characterized by TOWER and zinc finger (ZF) domains. The tower domain of KDM1A divides the AOL domain into two halves and is involved in interactions with different protein complexes [18]

Fig. 3

KDM1A interacting partners and functional diversity. The microenvironment of KDM1A contains various protein complexes (e.g., CoREST, NuRD, and RCOR2), receptors (estrogen, androgen, and TLX), noncoding RNAs (HOTAIR, SRA and TERRAs), microRNAs (miR-137 and miR-329), nonhistone proteins (p53, E2F1, and DNMT1) and transcription factors (TLA and SNAIL). The interaction of KDM1A with these diverse factors allows the dynamic regulation of different biological processes through the suppression and the activation of target gene expression depending upon the type of its interacting partner, i.e., the interaction of KDM1A with miR-137 downregulate the expression of KDM1A and in turn led to the differentiation of cells by activating the associated genes while its association with CoREST results in downregulation/suppression of target genes

Fig. 4

Substrate specificity and regulation of gene expression by KDM1A. The binding of KDM1A to the CoREST and NuRD complex allows the demethylation of H3K4me1/2 and leads to the inhibition of target gene expression, but this complex cannot catalyze the demethylation of the lysine 9 of histone 3 (H3K9me1/2). The interaction between KDM1A and the androgen and estrogen receptors alters its substrate specificity from H3K4me1/2 to H3K9me1/2, allowing for the regulation of target gene expression [18]

Fig. 5

Role of KDM1A in epithelial–mesenchymal transition. SNAI1 recruits the KDM1A corepressor complex, leading to the demethylation of H3K4me2 in the histone tails of E-cadherin-associated promoters. This demethylation ultimately inactivates these E-cadherin associated promoters. This SNAI1-mediated interaction of KDM1A with E-cadherin controls the processes of neural development and tumorigenesis