Role of Histone Lysine-Specific Demethylase 1(Lsd1) in Cancer Therapy

Epigenetic gene regulation is one of the important mechanisms for eukeryotic cells to regulate gene expression. These epigenetic modifications, including DNA methylation, histone methylation and histone acetylation, regulate the local chromatin architecture and direct gene expression. Epigenetic modifications regulate a subset of genes involved in cell growth and survival, and play a critical role in the regulation of cell proliferation, differentiation and tissue development. Aberrant epigenetic modifications have been shown to play a significant role in the initiation and progression of human malignancies. Histone lysine-specific demethylase 1 (LSD1) is the first enzyme found to catalyze the demethylation of histone H3K4 and H3K9, resulting in the remodeling of local chromatin structure and function, and modulating gene expression. In order to understand whether LSD1 is involved in tumor pathogenesis, and to assess the potential of targeting LSD1 for cancer treatment, we conducted a meta-analysis using the public available microarray database to evaluate the expression levels of LSD1 in clinical cancer tissues. Preliminary studies have shown that expression level of LSD1 is significantly elevated in majority of tumor tissues except for few cancer types, such as breast cancer. Our in-house immunohistochemistry study also detected a dramatic increase in the nuclear staining intensity of LSD1 protein in tumor cells. To further elucidate the roles of LSD1 in the growth and survival of tumor cells, we utilized small interfering RNA technology to knockdown the expression of LSD1 protein. Treatment with LSD1 siRNA effectively inhibited cancer cell growth, suppressed their colony forming capability, and induced a cell cycle arrest at G1 phase. Moreover, microarray analysis of the global gene expression pattern revealed that, LSD1 knockdown significantly altered the expression levels of genes involved in cell cycle progression and growth factor-mediated signaling. These results indicate that LSD1 is required for the growth of tumor cells and plays an oncogenic role in tumor pathogenesis, and that inhibition of LSD1 can effectively suppress the growth of tumor cells. This proposal aims to investigate the role of LSD1 in tumor pathogenesis and to evaluate the feasibility of using LSD1 as the molecular target for anticancer treatment. We plan to screen a panel of cancer cell lines for their LSD1 levels and their response to LSD1 inhibition in order to identify tumor types suitable for LSD1 inhibitor-based anticancer treatment. We will also conduct in vitro functional assays and in vivo tumor xenograft models to identify effective therapeutic regimen of LSD1 inhibitor-based treatment, either use alone or in combination with other approved epigenetic modulating agents. Finally, to identify novel lead structure for future chemical optimization, we plan to establish an enzyme-based demethylase assay and screen a compound library to discover novel LSD1 inhibitors. Results of this project will help to uncover the relationship between LSD1 and the genes and networks regulated by LSD1 in cancer cell growth and survival. This study will also help to define the target cancer types suitable for LSD1 inhibitor-based treatment. The novel LSD1 inhibitors identified could also provide an additional choice for future cancer treatment.

Project ID:PC10101-1448
External Project ID:NSC99-2320-B182-016-MY3