Lim, Soyoung: Lysine-specific histone demethylase 1 (LSD1) : A novel molecular target for tumor therapy. - Bonn, 2010. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5N-19562
@phdthesis{handle:20.500.11811/4161,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5N-19562,
author = {{Soyoung Lim}},
title = {Lysine-specific histone demethylase 1 (LSD1) : A novel molecular target for tumor therapy},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2010,
month = jan,

note = {Aberrant epigenetic changes in DNA methylation and histone acetylation are hallmarks of most cancers, while histone methylation had been considered to be irreversible and less versatile. Recently, several histone demethylases were identified catalyzing the removal of methyl groups from histone H3 lysine residues and thereby influencing gene expression. Lysine-specific histone demethylase 1 (LSD1) modulates demethylation of mono- and dimethylated lysines at residues 4 or 9 in histone H3, thereby allowing transcription factors or co-repressor complexes to selectively initiate or repress transcription. Although the physiological role of histone methylation is actively investigated, little is known about the implication of LSD1 in tumorigenesis. Here, we addressed the functional significance of LSD1 in different tumor types.
Neuroblastoma is the most common extracranial tumor of childhood originating from undifferentiated precursor cells of the peripheral sympathetic nervous system. Despite advances in multimodal therapy, neuroblastomas remain a clinical challenge. In this work, we found that LSD1 is strongly expressed in very aggressive neuroblastomas. LSD1 expression was inversely correlated with differentiation in primary neuroblastic tumors and correlated with adverse clinical outcome. In vitro differentiation of neuroblastoma cells resulted in downregulation of LSD1, suggesting that LSD1 is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells. siRNA-mediated knock-down of LSD1 decreased cellular growth and induced expression of differentiation-associated genes like TNS1, TPM1, DNM2 and DNAL4. Upon knock-down of LSD1, putative tumor suppressor genes like TFPI2 and XRCC5 were increased accompanied by the increase in target gene specific H3K4 methylation. Since the catalytic domain of LSD1 has a high sequence homology to monoaminoxidases (MAOs), MAO inhibitors (MAOIs) were reported as LSD1 inhibitors. LSD1 inhibition using MAOIs resulted in an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells in vitro. A xenograft mouse model was used to assess the potential therapeutic value of targeting LSD1 in neuroblastic tumor in vivo. For the first time, we could show that the treatment with MAOI tranylcypromine reduced significantly xenograft tumor growth, suggesting that LSD1 may serve as a drug target in neuroblastoma. However, MAOIs were shown to be inadequate for tumor treatment due to their excessive side effects such as seizures caused by their modulation of neurotransmitter deamination. Instead, specific LSD1 inhibitors must be developed which do not inhibit type A and B MAOs.
In industrialized countries, breast cancer is the most common tumor in women. Expression level of estrogen receptors (ERs) is an important predictive diagnostic marker indicating a favourable clinical course and response to hormone therapy. In this work, I developed an ELISA to examine LSD1 protein levels in tissue specimens of breast cancer. We determined very high LSD1 expression in ER-negative tumors which are known to have a poorer prognosis than ER-positive tumors. Pharmacological LSD1 inhibition resulted in growth inhibition of breast cancer cells. Genetic knock-down of LSD1 induced downregulation of proliferation-associated genes such as CCNA2 and ERBB2 and increased target gene-specific H3K9 methylation. These data indicate that LSD1 may serve as a predictive marker for aggressive biology and targeting LSD1 in ER-negative breast cancers might provide more specific treatment. In summary, I could show that LSD1 is strongly expressed in malignant neuroblastoma and breast cancer and functions as an oncogene.
Although histone methylation has been shown to be implicated in tumorigenesis, to date, no specific chemical modulator of LSD1 has been described. To identify selective LSD1 inhibitors from a compound library comprising 768 compounds selected by cheminformatics approach, a LSD1-HRP coupled assay was developed and applied for a high-throughput kinetic study. In this screening, a putative LSD1 inhibitor was identified and further experiments are going on to evaluate its LSD1 inhibitory actions. The identification of a new LSD1 inhibitor may serve as a starting point toward the development of a new class of LSD1 inhibitors which would help to evaluate the therapeutic potential of targeting LSD1 for tumor therapy.},

url = {http://hdl.handle.net/20.500.11811/4161}
}

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