Role of ASXL1 in Tumorigenesis and EMT in Breast Cancer
by Anusha Budida
Date of Examination:2016-12-15
Date of issue:2017-06-22
Advisor:Prof. Dr. Steven Johnsen
Referee:Prof. Dr. Michael Zeisberg
Referee:Prof. Dr. Claudia Binder
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Abstract
English
Breast cancer is one of the types of cancer that occurs in women frequently and most of the cancer deaths are due to metastasis. During cancer metastasis, the tumor epithelial cells lose their cell-cell contacts, acquire mesenchymal, migratory and invasive characteristics through epithelial-to-mesenchymal transition (EMT). Although many studies shed light on the mutations of ASXL family members in several cancers but the mechanism of action and the regulation remained poorly understood. ASXL1 is considered as a novel type of tumor suppressor in myeloid malignancies, which acts through the regulation of cell proliferation. In this study, we showed that the depletion of ASXL1 in normal mammary epithelial cells leads to the loss of epithelial characteristics and gain stem cell-like, migratory and metastatic properties, which is characterized by the increased expression of the mesenchymal markers and decreased expression of the epithelial markers. Global RNA-seq transcriptome analysis revealed an enrichment of gene signatures associated with a mammary stem cell phenotype and EMT pathways upon ASXL1 knockdown. We also examined the genome-wide binding of ASXL1 via ChIP sequencing and identified a preferential occupancy of ASXL1 near transcriptional start sites of a subset of ASXL1 target genes. From our results, we found PTEN as a target gene and the depletion of PTEN promotes EMT phenotype. Depletion of ASXL1 decreases the enrichment of H3K4me3 at the promoters of target genes. ASXL1 is physically interacting with methyltransferase SET1 complex members (Cfp1 and Wdr82) and it might be required for the maintenance of the cellular expression of SET1 complex members (Cpf1 and Wdr82). Taken together, our results suggest that ASXL1 is a tumor suppressor and negatively regulates EMT. ASXL1 might promote transcription of a subset of ASXL1 affected genes either by directly binding to the target genes or through the active mark, H3K4me3 on the promoters. Further studies may provide additional insight which may be useful for developing new therapeutic targets for preventing or treating breast cancer metastasis.
Keywords: Molecular medicine