Abstract
Lysine specific demethylase 1 (LSD1) functions as a transcriptional repressor through demethylating active histone marks such as mono- or di-methylated histone 3 lysine 4 (H3K4) and interacting with histone deacetylases. However, LSD1 can also act as an activator through demethylating repressive histone marks and possibly non-histone proteins. In prostate cancer (PCa) cells, LSD1 mediates the transcriptional activity of androgen receptor (AR), a ligand dependent nuclear transcription factor that drives PCa initiation and progression to the castration-resistant prostate cancer (CRPC). However, it is unclear whether LSD1 also regulates other growth promoting pathways independent of AR signaling in PCa cells. In this study, we show that LSD1 can activate PI3K/AKT pathways in absence of androgen stimulation, and we further demonstrate that LSD1 transcriptionally regulates the expression of PI3K regulatory subunit, p85, possibly through epigenetic reprogramming of enhancer landscape in PCa cells. Our study suggests that LSD1 has dual functions in promoting PCa development, that it enhances AR signaling through its coactivator function, and that it activates PI3K/AKT signaling through increasing p85 gene expression.
Highlights
Lysine specific demethylase 1 (LSD1/KDM1A), a specific demethylase of mono- or di-methylated histone lysine 4 (H3K4me1,2, enhancer-associated histone marks), was first identified as a component of REST repressor complex through interaction with CoREST and histone deacetylases 1, 2 (HDAC1,2) [1, 2]
To determine whether PI3K/AKT pathway is activated by LSD1, we examined Ser473 phosphorylation of AKT, a marker for its full activation [17, 18], in LNCaP cells treated with GSK2879552 and our data indicated that LSD1 inhibition markedly decreased AKT phosphorylation (Figure 1C)
This provides a strong molecular basis to treat prostate cancer (PCa) tumor with LSD1 inhibitors and we are currently testing LSD1 inhibitor treatments in preclinical models of castration-resistant prostate cancer (CRPC)
Summary
Lysine specific demethylase 1 (LSD1/KDM1A), a specific demethylase of mono- or di-methylated histone lysine 4 (H3K4me, enhancer-associated histone marks), was first identified as a component of REST repressor complex through interaction with CoREST and histone deacetylases 1, 2 (HDAC1,2) [1, 2]. In prostate cancer (PCa) cells, LSD1 functions as a major androgen receptor (AR) coactivator [5, 9]. This activity was thought to be attributed to androgen-induced phosphorylation of histone 3 threonine 6 and 11 (H3T6/T11ph), which lead to the switch of LSD1 substrate from H3K4me to H3K9me1,2 [5, 10,11,12].
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