Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer

Abstract

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA.

Keywords: LSD1; cancer; epigenetics; histone demethylase; lncRNAs.

Figure 1

(a) Demethylase 1 (LSD1) is recruited at the target gene by a wide number of transcription factors (indicated in figure) where it promotes the transcriptional repression through demethylation of the H3K4me2 activation mark. (b) LSD1 demethylates the repressive mark H3K9me2 as coactivator with the androgen or estrogen receptor. (c) LSD1+8a, a neuronal-specific isoform, catalyzes the demethylation of the repressive mark H4K20me2, by interacting with CREB and MEF2.

Figure 2

LSD1 regulates methylation dynamics of non-histone proteins.

Figure 3

LSD1-dependent demethylation regulates activity of non-histone proteins. Effects of LSD1-mediated demethylation of non-histone proteins p53-E2F1 and PPP1R12A (a), HIF-1α (b), and AGO2 (c).

Figure 4

(a) HOTAIR mediates target gene silencing; it binds to PRC2 complex (EZH2, SUZ12, EEDs) and LSD1 complex (CoREST/REST) through binding at 5′ and 3′ ends, respectively, regulating trimethylation of H3K27me3 and demethylation of H3K4me2. (b) TERRA RNA modulates telomeric gene silencing through recruitment of LSD1 on uncapped telomeres, reinforcing the interaction between LSD1 and MRE11. (c) SRA interacts with the repressive complex LSD1-HP1γ-HDAC1/2-CoREST (LSD1.com) and brings this complex on target chromatin, promoting aberrant hormone-regulated gene expression.