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Page 2 of 9 Saccà et al. J Cancer Metastasis Treat 2019;5:15 I http://dx.doi.org/10.20517/2394-4722.2018.95

A

B

Figure 1. Lysine specific demethylase 1 (LSD1) protein domains and structure. A: In orange the SWIRM domain, in green the AOD
domains and in yellow the Tower Domain; B: LSD1 selective substrate specificities: LSD1 represses promoter and enhancer activities
through the demethylation of histones lysines, H3K4 or in cooperation with the androgen receptor (AR), activates transcription through
Histones H3K9 demethylation

[2]
The major causes of death in breast cancer patients are the result of metastasis in distant organs . Metastasis
is a complex biological process, which occurs through a series of steps: (1) rising of a locally invasive and
migratory behavior, (2) arriving to the blood vessel and into the circulation via the blood flow, (3) halting
[2,3]
in the distant organ, (4) surviving the initial stress, and (5) reinitiating outgrowth in distant stroma .
[3]
Metastasis involves a multitude of molecular signals . Single cells leaving the primary tumor undergo
epithelial to mesenchymal transition (EMT), consisting in the loss of epithelial polarity and the achievement
[4]
of a mesenchymal morphology . The opposite process, the mesenchymal to epithelial transition, takes place
[5]
when metastatic cells switch back to an epithelial state in order to colonize secondary sites .
The mechanism of EMT is currently a major focus in metastasis research. The knowledge of its mechanisms
is still fragmentary and more in-depth studies are needed in order to improve therapeutic approaches and
[6,7]
influence, in the long-term, control of breast cancer outcome .
According to the reversible nature of EMT-associated processes, epigenetic mechanisms, such as DNA
methylation and histone modifications, exert a great influence on the EMT program [8-11] . Particularly, wide
ranges of studies demonstrate that the lysine specific demethylase 1 LSD1, also known as KDM1A, plays a
pivotal role in the EMT regulation [12-15] .

High levels of LSD1 expression in various tumors, including breast cancer, are correlated with poor
prognosis [16-19] ; several works reported that the ablation of LSD1 in breast cancer cells inhibits the invasion
capabilities and suppresses their metastatic potential [20-22] .

[23]
LSD1 is classified as an amine oxidase that uses FAD as the co-factor for its enzymatic action ; LSD1
is composed by three major domains: an N-terminal SWIRM (small alpha-helical domain), for protein
stability; a central protruding Tower domain and a C-terminal amine oxidase like domain [Figure 1A];
LSD1 is able to demethylate mono and di-methylated lysine 4 and 9 of the histone H3 (H3K4, H3K9) [23-27] .
Exerting its activity LSD1 can function as co-repressor, removing H3K4 methylation on gene promoters
and enhancers, or co-activator, by removing H3K9 methylation, indicating that substrate specificity and the
[12]
binding to different interactors define its biological outcome [Figure 1B] . Furthermore, LSD1 regulates
methylation dynamics of non-histone proteins [16,28-33] .