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.

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

“…The TLX-LSD1/RCOR2 axis is functional both in NSPCs and GSCs, where it positively regulates stemness gene expression (Sox2, Oct4). Finally, the frequently promoting effect of LSD1 inhibition on the differentiation of normal SCs is increasingly used as a therapeutic approach in the most undifferentiated and aggressive human malignancies (AML, glioblastoma, or HCC) [121,131,132] with promising preclinical outcomes, validating their entry into clinical trials (Tables 1 and 2).…”

“…However, it should be pointed out that these clinical studies do not include functional assays that can assess this parameter yet. Similarly, in most of the pre-clinical studies on LSD1 inhibition [83,131,132] the outcome is usually evaluated through its bulk characteristics i.e., tumor growth/volume, survival, dosing, and toxicity, leaving the effect on the CSC content elusive, with a few exceptions [105,106]. In our opinion, the solid findings provided by the basic research reports we presented herein prove that the regulation of CSCs by LSD1 is an important aspect of its role in cancer and it should be evaluated in all preclinical and clinical future studies.…”

LSD1 Inhibition Attenuates Tumor Growth by Disrupting PLK1 Mitotic Pathway

“…LSD1 was the first histone lysine demethylase discovered, and since then it has been attributed to play various biological roles in different cellular processes (8,32). LSD1 is remarkably overexpressed in a variety of tumor types and its expression correlates with aggressive tumor biology (33,34). Therefore, because of its widespread functions in various cancers, disrupting LSD1 signal effect in human malignancies is a potential novel therapeutic option.…”

Circulating microRNAs in Early Breast Cancer Patients and Its Association With Lymph Node Metastases

“…H3K9 methylation has been associated with the EMT through interactions of KDM1A (a H3K9 demethylase) with the members of the SNAI1 family of zinc nger transcription factors, including SNAI1 (SNAIL) and SNAI2 (SLUG). The expression of SNAI1 and Ecadherin is a hallmark of carcinoma development and metastasis (59). Our data suggest that that MiR-101 could be involved in the regulation of these pathways, as it has been shown to directly target the histone methyltransferase enhancer of zeste homologue 2 (EZH2), which could promote tumor proliferation and invasion (60) Circulating miR-133a expression was elevated in plasma samples from early-stage BC patients compared to healthy donors (61, 62) and similar results were reported for circulating miR-1307-3p (63) whereas downregulation of miR-376c-3p (64) miR-376c-3p have been linked to breast cancer recurrence (24).…”