4.1 Link of LSD1/2 to Cancer
LSD1 is overexpressed in various cancer cells and tissues, such as neuroblastoma
[25], prostate cancer [7, 26], breast cancer [27–29], lung cancer [30], and bladder
cancer cells [30]. Furthermore, the results of RNAi-mediated knockdown or LSD1
inhibition suggest that this enzyme is associated with cancer cell growth by modulating pro-survival gene expression and p53 transcriptional activity [25, 27, 31].
Schulte et al. reported that LSD1 expression is correlated with adverse outcome in
neuroblastic tumors [25]. The RNAi-mediated knockdown of LSD1 suppresses cell
growth, and LSD1 inhibition results in growth inhibition of neuroblastoma cells in
both in vitro and in vivo assays. In prostate cancer cells, AR binds an enhancer in the
AR second intron and represses AR gene expression through LSD1 recruitment and
H3K4me1/2 demethylation [32]. It was also reported that LSD1 is involved in breast
cancer proliferation in estrogen receptor α (ERα)-dependent and ERα-independent
manners [33]. Whereas LSD1 interacts with ERα in ERα-positive breast cancer cells
[34], it is highly expressed also in ER-negative breast cancer cells, and the pharmacological LSD1 inhibition or knockdown of LSD1 using small interfering RNA
(siRNA) results in the growth inhibition of ER-negative breast cancer cells and
induces the regulation of several proliferation-associated genes, such as p21,
ERBB2, and CCNA2 [28]. LSD1 expression is higher also in lung cancer tissue
than normal lung tissue [35]. The overexpression of LSD1 protein is associated with
shorter overall survival in non-small cell lung cancer (NSCLC) patients, and the
interruption of LSD1 using siRNA or chemical LSD1 inhibition suppresses the
proliferation, migration, and invasion of NSCLC A549, H460, and 293T cells. It
has been reported that LSD1 is overexpressed in leukemia cells and is involved in
leukemia cell proliferation and differentiation [36]. Importantly, LSD1 is closely
associated with the growth of cancer cells with pluripotent stem cell properties
expressing Oct4 and SOX2 [37–39].
It has also been reported recently that LSD2 is involved in breast cancer progression [40]. LSD2 protein level is significantly elevated in malignant breast cancer cell
lines compared with normal breast epithelial cell lines. Whereas the overexpression
of LSD2 in MDA-MB-231 cells significantly promotes cell proliferation, the
siRNA-mediated knockdown of endogenous LSD2 inhibits the growth of multiple
breast cancer cell lines, suggesting the critical role of LSD2 in the regulation of
breast cancer progression.
4.2 Link of LSD1 to Viral Infection
LSD1 regulates viral gene transcription [41]. In herpes simplex virus (HSV) and
varicella zoster virus (VZV), an increase in H3K4 methylation and a decrease in
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
201
LSD1 is overexpressed in various cancer cells and tissues, such as neuroblastoma
[25], prostate cancer [7, 26], breast cancer [27–29], lung cancer [30], and bladder
cancer cells [30]. Furthermore, the results of RNAi-mediated knockdown or LSD1
inhibition suggest that this enzyme is associated with cancer cell growth by modulating pro-survival gene expression and p53 transcriptional activity [25, 27, 31].
Schulte et al. reported that LSD1 expression is correlated with adverse outcome in
neuroblastic tumors [25]. The RNAi-mediated knockdown of LSD1 suppresses cell
growth, and LSD1 inhibition results in growth inhibition of neuroblastoma cells in
both in vitro and in vivo assays. In prostate cancer cells, AR binds an enhancer in the
AR second intron and represses AR gene expression through LSD1 recruitment and
H3K4me1/2 demethylation [32]. It was also reported that LSD1 is involved in breast
cancer proliferation in estrogen receptor α (ERα)-dependent and ERα-independent
manners [33]. Whereas LSD1 interacts with ERα in ERα-positive breast cancer cells
[34], it is highly expressed also in ER-negative breast cancer cells, and the pharmacological LSD1 inhibition or knockdown of LSD1 using small interfering RNA
(siRNA) results in the growth inhibition of ER-negative breast cancer cells and
induces the regulation of several proliferation-associated genes, such as p21,
ERBB2, and CCNA2 [28]. LSD1 expression is higher also in lung cancer tissue
than normal lung tissue [35]. The overexpression of LSD1 protein is associated with
shorter overall survival in non-small cell lung cancer (NSCLC) patients, and the
interruption of LSD1 using siRNA or chemical LSD1 inhibition suppresses the
proliferation, migration, and invasion of NSCLC A549, H460, and 293T cells. It
has been reported that LSD1 is overexpressed in leukemia cells and is involved in
leukemia cell proliferation and differentiation [36]. Importantly, LSD1 is closely
associated with the growth of cancer cells with pluripotent stem cell properties
expressing Oct4 and SOX2 [37–39].
It has also been reported recently that LSD2 is involved in breast cancer progression [40]. LSD2 protein level is significantly elevated in malignant breast cancer cell
lines compared with normal breast epithelial cell lines. Whereas the overexpression
of LSD2 in MDA-MB-231 cells significantly promotes cell proliferation, the
siRNA-mediated knockdown of endogenous LSD2 inhibits the growth of multiple
breast cancer cell lines, suggesting the critical role of LSD2 in the regulation of
breast cancer progression.
4.2 Link of LSD1 to Viral Infection
LSD1 regulates viral gene transcription [41]. In herpes simplex virus (HSV) and
varicella zoster virus (VZV), an increase in H3K4 methylation and a decrease in
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
201