Identifying Novel SUMO Regulators of TGF Beta-induced EMT and Breast Cancer Invasion

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Epithelial-mesenchymal transition (EMT) is a fundamental developmental process, which is reactivated in cancer contributing to tumor invasiveness and metastasis. The secreted factor transforming growth factor β (TGFβ) is a potent inducer of EMT in development and cancer. The transcriptional regulator SnoN and E3 ubiquitin ligase Smurf2 control TGFβ signalling in a complex manner with implications for cancer development and progression. The focus of my doctoral studies has been to examine the nature and regulation of SnoN and Smurf2 functions in TGFβ-induced EMT. In this regard, I have characterized the role of SUMO pathway in modifying both SnoN and Smurf2, thereby regulating their roles in controlling EMT. I employed three-dimensional (3D) model systems to follow EMT in mammary epithelial cells and invasive growth behavior of breast cancer cells to increase the chance of getting results with in-vivo relevance. My studies have led to the identification of the protein TIF1γ as a novel SUMO E3 ligase that promotes SnoN sumoylation. Importantly, my data show that TIF1γ acts via SnoN sumoylation to suppress TGFβ-induced EMT in 3D-mammary epithelial cell-derived acini. Next, I found that Smurf2 suppresses EMT in 3D cultures of epithelial cells. Also, I discovered that the SUMO pathway modifies Smurf2 at specific lysine residues through the SUMO E3 ligase PIAS3. Importantly, my data suggest that sumoylation is critical for Smurf2 to suppress TGFβ-induced EMT. Mechanistically, I found that sumoylation promotes Smurf2-induced degradation of TGFβ receptors, leading to suppression of TGFβ signalling and EMT. Lastly, my latest findings suggest that the PIAS3-Smurf2 sumoylation pathway suppresses TGFβ-induced invasive growth of 3D-breast cancer cell-derived spheroids. Future studies, using a xenograft cancer model will aim to investigate role of the PIAS3-Smurf2 sumoylation pathway in tumorigenesis. Overall, our research questions have led to the identification of novel regulators of TGFβ-induced EMT and potentially breast cancer invasion and metastasis. Importantly, SUMO-based pathways promote the ability of both SnoN and Smurf2 to suppress TGFβ-induced EMT in mammary epithelial cells, with relevance to cancer cell invasion and metastasis. Our findings could help in providing potential new diagnostic or druggable targets for treatment of breast tumors.
Biology, Biology--Cell, Biology--Molecular, Human Development, Oncology, Biochemistry
Chandhoke, A. S. (2016). Identifying Novel SUMO Regulators of TGF Beta-induced EMT and Breast Cancer Invasion (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from doi:10.11575/PRISM/26433