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Page 4 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

C D

Figure 2. Lysine specific demethylase 1 (LSD1) regulates cell motility and epithelial to mesenchymal transition (EMT). A: Snail is stabilized
through the formation of a ternary Snail1-LSD1-CoREST complex. SNAG domain of Snail binds LSD1 and recruits it together with CoREST
to E-boxes of Snail target gene promoters. LSD1 binds the histones H3 tail and removes the activation marks on H3K4. HDAC1 and 2
deacetylate histones 3 and 4 (H3/H4), subsequently PRC2 directs the trimethylation of H3K27; B: H3K9 demethylation activity by LSD1
in complex with ERRα leads to transcriptional activation of pro-invasive genes; C: LSD1 inhibits EMT process through binding to NuRD
impairing TGF-β signaling genes expression. D LSD1 with UTX functions as epigenetic silencer of EMT TFs

[14]
[14]
(UTX) . UTX functions as lysine-specific demethylase on H3K27me2/H3K27me3. Choi et al.
demonstrated that the role of UTX in epigenetic silencing of EMT-TF is not due to its H3K27 demethylation
activity but to the ability to disrupt c-Myc and MLL4 recruitment on the E-boxes of their promoters. LSD1
recruited by UTX on the E-boxes form a transcriptional repressive complex with histone deacetylase 1
(HDAC1) and DNA methyltransferase 1 (DNMT1) [Figure 2D]. LSD1 together with UTX in this case of
human breast cancers functions directly as epigenetic silencer of EMT TFs and consequently acts as tumor
[14]
suppressor .

LSD1 POST-TRANSLATIONAL TARGETING IN EMT MODULATION
Several studies established that LSD1 activity and stability is altered by post-translational modifications [40,41] .
LSD1 is acetylated in epithelial, but not in mesenchymal cells. In particular, the acetyltransferase MOF (or
[21]
KAT8, lysine acetyltransferase 8) is critically involved in LSD1-induced EMT, acting on LSD1 acetylation .
MOF-mediated acetylation of LSD1 on lysines 432, 433 and 436 alters the association between LSD1 and
target chromatin loci, increasing H3K4me2 levels and expression of epithelial markers. Moreover, while
LSD1 is ubiquitously expressed, MOF is enriched in epithelial cells, but down-regulated in mesenchymal
[21]
cells . Thus, MOF-mediated acetylation of LSD1 may represent a crucial regulatory switch that, modulating
LSD1 control of the EMT process. Accordingly, in epithelial breast cancer cells, MOF blocks LSD1
association with epithelial gene promoters, increases H3K4me2 levels at these loci and activates E-cadherin
[21]
expression [Figure 3A].

In addition, recent evidences highlight that phosphorylation of LSD1 on Serine-111 (analogous to murine
serine-112) is crucial for its activity in the EMT programs. It has been reported that PKCα (Protein kinase