Disease relevance of AOF2

• Treatment of P19 embryonal carcinoma cells with tranylcypromine resulted in global increase in H3K4 methylation as well as transcriptional derepression of two BHC110 target genes, Egr1 and the pluripotent stem cell marker Oct4 [1].

High impact information on AOF2

• The recently identified histone demethylase lysine-specific demethylase 1 (LSD1) is chemically restricted to demethylation of only mono- and di- but not trimethylated histone H3 lysine 4 (H3K4me3) [2].
• Histone methylation is dynamically regulated by histone methylases and demethylases such as LSD1 and JHDM1, which mediate demethylation of di- and monomethylated histones [3].
• They showed that LSD 1, a nuclear amine oxidase homolog, is a bona fide histone H3 lysine 4 demethylase (Shi et al., 2004) [4].
• LSD1-CoREST forms an elongated structure with a long stalk connecting the catalytic domain of LSD1 and the CoREST SANT2 domain [5].
• LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged pocket at the active site and possibly a shallow groove on its surface [5].

Biological context of AOF2

• Importantly, RNAi inhibition of LSD1 causes an increase in H3 lysine 4 methylation and concomitant derepression of target genes, suggesting that LSD1 represses transcription via histone demethylation [6].
• Compound 1 is thus a selective, mechanism-based inactivator of LSD1 and is likely to serve as a useful tool in the study of histone modifications and chromatin remodeling [7].

Associations of AOF2 with chemical compounds

• Here we show that BHC110-containing complexes show a nearly fivefold increase in demethylation of histone H3 lysine 4 (H3K4) compared to recombinant BHC110 [8].
• Furthermore, we identify pargyline as an inhibitor of LSD1 [9].
• We previously identified LSD1 and FHL2 as nuclear cofactors interacting specifically with the AR in prostate cells and showed that both stimulate androgen-dependent gene transcription [10].
• The polypeptide composition of these complexes has in common a core of two subunits, HDAC1,2 and BHC110, an FAD-binding protein [11].
• Histone demethylation catalysed by LSD1 is a flavin-dependent oxidative process [12].

Physical interactions of AOF2

• LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription [9].

Regulatory relationships of AOF2

• LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription [9].
• While CoREST positively regulates LSD1 function, BHC80 inhibits CoREST/LSD1-mediated demethylation in vitro and may therefore confer negative regulation [13].

Other interactions of AOF2

• Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription [9].
• Recently, the LSD1 protein, which bears a SWIRM domain, was found to be a demethylase for Lys4-methylated histone H3 [14].
• Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used [15].
• Our data reveal that high levels of LSD1, nuclear expression of the FHL2 coactivator, high Gleason score and grade, and very strong staining of nuclear p53 correlate significantly with relapse during follow-up [10].

Analytical, diagnostic and therapeutic context of AOF2

• Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner [9].

References