Targeting LSD2 in breast cancer

Histone lysine demethylases (KDMs) are family of enzymes which are involved in the extensive epigenetic modification in many cellular processes such as transcription regulation, chromatin remodeling, DNA proofreading and repair, cellular proliferation, embryotic development, etc [1, 2]. To date, two families of histone demethylases (KDMs) have been discovered; the flavin-dependent lysine specific demethylases and the JmjC-domain containing KDMs. The flavindependent KDM family includes LSD1 (KDM1A/AOF2) and LSD2 (KDM1B/AOF1). Both enzymes contain a SWIRM domain and an amine oxidase (AO) domain. Structurally, LSD1 contains a coiled-coil tower domain protruding from the AO domain responsible for interaction with its co-factors, while LSD2 possesses an aminoterminal zinc finger element that is necessary for LSD2 binding to its methylated substrate. Both enzymes catalyze histone demethylation through a flavindependent oxidative process that generates a demethylated lysine 4 of histone 3 and H2O2 as a byproduct. Although LSD1 and LSD2 share significant homology of amino acid sequence in the AO domain and both enzymes demethylate lysine 4 on histone 3 in a FAD-dependent manner, it is apparent that the two enzymes also have distinct functions, and therefore may act differently in regulation of gene transcription and chromatin remodeling (Figure 1). While LSD1 mostly binds to the promoter region of genes, LSD2 associates primarily with the body regions of actively transcribed genes. LSD1 typically participates in transcriptional repression as part of a protein complex that contains multiple transcriptional corepressors including HDAC1/2, CoREST, BHC80, etc. The dysregulated transcriptional repressive activity of LSD1 complex has been implicated in cancer initiation and progression [3, 4]. While the activities of LSD1 in promoting breast cancer progression have been well recognized, the functions of LSD2 in breast tumorigenesis are relatively less characterized. In our recent published research article, we reported that the level of LSD2 expression is significantly increased in breast cancer specimens in comparison to normal adjacent tissue, and LSD2 expression in invasive breast tumors is greater than that of non-invasive counterparts [5]. These findings indicate a tumor promoting role of LSD2 in breast cancer biology. Editorial