Histone demethylase LSD1 controls the phenotypic plasticity of cancer cells

Abstract

Epigenetic mechanisms underlie the phenotypic plasticity of cells, while aberrant epigenetic regulation through genetic mutations and/or misregulated expression of epigenetic factors leads to aberrant cell fate determination, which provides a foundation for oncogenic transformation. Lysine‐specific demethylase‐1 (LSD1, KDM1A) removes methyl groups from methylated proteins, including histone H3, and is frequently overexpressed in various types of solid tumors and hematopoietic neoplasms. While LSD1 is involved in a wide variety of normal physiological processes, including stem cell maintenance and differentiation, it is also a key player in oncogenic processes, including compromised differentiation, enhanced cell motility and metabolic reprogramming. Here, we present an overview of how LSD1 epigenetically regulates cellular plasticity through distinct molecular mechanisms in different biological contexts. Targeted inhibition of the context‐dependent activities of LSD1 may provide a highly selective means to eliminate cancer cells.

Phosphorylation of LSD1 by PLK1 promotes its chromatin release during mitosis

“…Tipping the balance toward either direction could be detrimental. For example, LSD1 serves for demethylation of H3K4 and H3K9 [5], its gene deletion was reported in pancreatic ductal adenocarcinoma (7/109 = 6.4%) [19], while its gene amplification was found in neuroendocrine prostate cancer (6/107 = 5.6%) (http://www.cbioportal.org/) and sarcoma (6/207 = 2.9%) [20]. LSD1 RNA expression levels vary a lot in different cancer types (http://www.cbioportal.org/).…”

“…Lysine-specific demethylase 1 (LSD1), a flavin adenine dinucleotide (FAD)-dependent amine oxidase, was the first identified demethylase (eraser) for lysine methylation of histones and non-histone proteins [5]. It specifically removes methyl groups via a redox process of mono- or di-methylated histone H3 lysine4 (H3K4) [6] and H3 lysine 9 (H3K9) [7].…”

“…On the other hand, LSD1 is recruited to the promoter regions of androgen receptor (AR) target genes and demethylates H3K9me, co-activating AR-dependent transcription [7]. Misregulated expression of LSD1 has been reported in several cancer types [5, 8]. …”

Hepatoepigenetic Alterations in Viral and Nonviral-Induced Hepatocellular Carcinoma

“…LSD1 is frequently overexpressed in HCC cells and promotes tumorigenesis by epigenetically dysregulating EMT and glycolytic and mitochondrial metabolism [70, 71]. JMJD1A is an important regulator of hypoxia-inducible transcription factor and also stimulates tumour growth.…”

HOTAIR promotes an epithelial-to-mesenchymal transition through relocation of the histone demethylase Lsd1

“…However, little is known of whether and how Lsd1 contributes to HOTAIR action. Lsd1 is a well-known epigenetic regulator of EMT and cancer with, in few cases, a tumor suppression function (Wang et al, 2009), but mostly playing an oncogenic role (Hino et al, 2016), (Harris et al, 2012), (Sun et al, 2016), (Lim et al, 2010), (Schenk et al, 2012), (Feng et al, 2016). The functional duality of Lsd1 can be attributed to the versatility of its substrates and of Lsd1 interacting partners in different biological contexts (Shi et al, 2004), (Metzger et al, 2005), (McDonald et al, 2011).…”