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transcription factor 3 (TCF3, also known as E47) [47-49] . In this contest, LSD1 has a pivotal role in HIF-1α post-
translation regulation. LSD1 demethylates lysine 32 (K32) of HIF-1α, while the same site can be methylated
[50]
by SET9 inducing HIF-1α protein degradation [Figure 4A].
Moreover, in breast cancer, it has been reported that LSD1 regulates indirectly HIF-1α at post- translation
level influencing its stability and avoiding its degradation. In particular, LSD1 upregulates HIF-1α
demethylating the RACK1 (receptor for activated C kinase 1) protein (a component of the HIF-1α
ubiquitination machinery) on lysine 271 (K271). After that, the degradation of HIF-1α is suppressed. These
results indicate that in breast cancer the levels of FAD in the cells and the FAD-dependent LSD1 activity
[51]
on RACK1-K271me2 could be the main determinants of HIF-1α stability during prolonged hypoxia
[Figure 4B]. Accordingly, it has been shown that LSD1 inhibitors also impair the accumulation of HIF-1α,
which is implicated in the activation of EMT in breast cancer. Therefore, even if at the moment there is a lack
of evidences for an in vivo link between LSD1/HIF-1α/EMT, this pathway needs to be further explored since
FAD modulation could represent a potential therapeutic strategy to regulate LSD1 and HIF-1α pathway.

CONCLUSION
Oncogenic roles of LSD1 in the pathogenesis of different epithelial cancers, such prostate, bladder, liver, non-
small cell lung cancer and neuroblastomas, have been widely reported.

In breast cancer, LSD1 expression increases with cancer progression and its overexpression is positively
correlated with the estrogen receptor negative status; high levels of LSD1 are a considerate molecular marker
[17]
for predictive aggressive biology in ER-negative [17,24] and basal-like breast cancer. Moreover, the depletion
of LSD1 reduces proliferation and invasiveness of breast cancer cells in vitro.

In breast cancer, the oncogenic role of LSD1 depends on its versatility to interact with different partners.
Current clinical trials utilizing epigenetic drugs for combination therapy have been shown to be promising
[52]
in treating metastatic cancers. Vasilatos et al. suggest that the combination therapy of LSD1 and HDAC
inhibitors leads to expression activation of genes such as E-cadherin in Triple-negative breast cancer (TNBC) [52-54] .
[55]
More recently, Yang et al. proposed that LSD1 interacts with SIN3A/HDAC complex, which plays a role in
EMT-induced cancer stemness inhibiting a series of genes, such as TERT (Telomerase reverse transcriptase),
CUL4A (Cullin4A), TGFB2 (Transforming growth factor beta 2 ), MDM2 (Mouse double minute 2 homolog ),
[55]
RHOA (Ras homolog family member A) and HIF-1α .
Progresses have been made in drug targeting for breast cancer over the years. Current clinical treatments
typically involve surgery if disease is promptly diagnosed. Moreover, depending on molecular characteristics
of injury, breast cancer surgery may be followed by radiation, chemotherapy, hormone therapy and targeted
therapy. Nevertheless, the major limitation of targeted anticancer therapies is the intrinsic or acquired
[56]
resistance .

Epigenetic therapies are prime candidates for adjuvant treatments to improve cancer therapy efficacy. Thus,
establishing how exactly LSD1 regulates cell proliferation and invasive capacity will potentially facilitate the
development of epigenetic therapies to attenuate tumor progression and metastasis in human breast cancer.

Recent studies identify LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to
immunotherapy. LSD1 inhibition leads to double-stranded RNA stress and activation of type 1 interferon,
[57]
which stimulates anti-tumor T cell response and represses tumor growth .
[58]
Qin et al. have recently shown that the inhibition of LSD1 reactivates key immune checkpoint regulator
and cytotoxic T cell-attracting chemokines in TNBC to immune checkpoint blocking antibodies. In vivo,