Browsing by Author "Chanda, Ayan"

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    Regulation of Epithelial Cell Plasticity by a SUMO-TGFβ Signaling Axis
    (2019-12) Chanda, Ayan; Bonni, Shirin; Moorhead, Greg B. G.; Morris, Don G.; Arcellana-Panlilio, Mayi Y.; Godbout, Roseline
    Background Protein post-translational modification by the small ubiquitin-like modifier (SUMO), or SUMOylation, can regulate the stability, subcellular localization or interactome of a protein substrate with key consequences for cellular processes including the Epithelial-Mesenchymal Transition (EMT). The secreted factor Transforming Growth Factor beta (TGFβ) is a potent inducer of EMT in development and homeostasis. Importantly, the ability of TGFβ to induce EMT has been implicated in promoting cancer invasion and metastasis, resistance to chemo/radio therapy and maintenance of cancer stem cells. Interestingly, TGFβ-induced EMT and the SUMO system intersect with important implications for cancer formation and progression, and novel therapeutics identification. The transcriptional coregulator Ski-related novel protein N (SnoN), a negative regulator of TGFβ signaling axis, is a SUMO substrate. Interestingly, Protein Inhibitor of Activated STAT 1 (PIAS1) and Transcriptional Intermediary Factor 1 gamma (TIF1γ) are two distinct SUMO E3 ligases that bind and promote the SUMOylation of SnoN to suppress TGFβ-induced EMT. PIAS1 has been shown to act in a SUMO E3 ligase-dependent manner to suppress the invasion and metastatic growth of breast cancer cells. These results raised the key questions of the significance of the role of the two distinct SUMO E3 ligases PIAS1 and TIF1γ in regulating SnoN SUMOylation and suppressing TGFβ-induced EMT in mammary non-transformed epithelial cells and breast carcinomas. Hypothesis I hypothesize that PIAS1 and TIF1γ cooperate to promote SnoN SUMOylation to suppress EMT by the TGFβ-Smad pathway with potential relevance for breast cancer metastasis and prognosis. Results In this thesis, evidence is provided suggesting that the protein abundance and nuclear localization of PIAS1 act as survival biomarkers in breast cancer patients in a tissue microarray analysis. Accordingly, further results indicate that PIAS1 acts via SUMOylation of SnoN to suppress the invasive growth of triple negative breast cancer cells in 3D-organoid culture. In other studies, findings are provided that support the idea that SnoN promotes the formation of PIAS1-SnoN-TIF1γ multiprotein complex, which promotes SnoN SUMOylation, and its ability to suppress TGFβ-induced EMT in breast epithelial and cancer cells in 3D. Mechanistic studies suggest that SUMOylation promotes SnoN binding to the epigenetic regulators histone deacetylase 1 (HDAC1) and histone acetylase p300 in such a manner that leads to the suppression of EMT induced by the TGFβ-Smad-pathway in non-transformed and cancerous mammary cell-derived 3D organoids. Conclusions The novel findings in this thesis reveal the importance of a SUMO E3 ligase complex comprising PIAS1 and TIF1γ that enhances the SUMOylation of SnoN with impact on specific epigenetic regulators that control EMT in normal and cancer cells. These findings can lead to the discovery of novel biomarkers and therapeutics in breast and potentially other epithelial cell-derived cancers.