Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA

Role of the histone demethylase LSD1 in Brain Tumor

Epigenetic enzymes are promising targets for cancer therapy due to their involvement in cellular processes leading to oncogenesis. Accordingly, a number of epi-drugs are currently under investigation. Lysine-specific demethylase 1 (LSD1) removes mono- and di-methylated groups from lysines 4 or 9 on histone H3, via a flavin adenine dinucleotide (FAD)-dependent oxidative reaction. In brain tumours, LSD1 is over-expressed and it is correlated with aggressive disease, suggesting that its inhibition might be considered as therapeutically relevant. The work done during my PHD has been focused on the understanding the role of LSD1 uncovering its potential functions as new potential therapeutic agent for neuroblastoma (NB) and glioblastoma (GBM) tumours. We have investigated on its role in different Brain tumours demonstrating that LSD1 depletion is involved in three tumour-associated pathways: Epithelial-mesenchymal-Transition (EMT); Autophagy and Senescence and that different pathways are affected in different Brain tumours. In conclusion, we propose that pharmacological targeting of LSD1 by small molecules could modulate autophagy, senescence, migration capability and invasiveness of cancer cells through targeting proteins and thus impairing the ability of cancers to metastasize

DDDR-32. A NEW IMMUNOMODULATORY FUNCTION OF PYRIDO-PYRIMIDINE DERIVATIVES TO IMPAIR METASTATIC GROUP 3 MEDULLOBLASTOMA IN VIVO

Medulloblastoma (MB) is an embryonal tumor of the cerebellum consti- tuting ~ 20% of pediatric brain tumors. To date, four MB molecular groups (further stratified in twelve subtypes) have been described. Among them, Groups 3 and Group 4 MB have the poorest prognosis due to their high metastatic potential. Recently, we have reported a metastatic axis driven by Prune1 overexpression in MB Group3 characterized by canonical TGF-β signaling enhancement and epithelial-mesenchymal transition. Here, we have developed a new not toxic pyrido-pyrimidine derivative with the ability to impair Prune-1-driven-axis, thus ameliorating the survival rate of a murine model of metastatic MB Group3 characterized by overexpression of human Prune1 gene in the cerebellum (under the control of MATH1 promoter). Of importance, this small molecule also is showing immunomodulatory functions thus inhibiting the conversion of tumor-infiltrating T lymphocytes (TILs) to immunosuppressive regulatory T cells (Tregs) in vivo via impairing the secretion of inflammatory cytokines from MB cells. Furthermore, this molecule can also act synergistically with the currently used modified- intensity chemotherapy (e.g. in PNET5 use of Vincristine) or potential in the combination with epigenetics drugs (e.g., LSD1/KDM1A inhibitors). Altogether these results are of importance for future targeted therapies of high-risk metastatic MB