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Plasminogen activator, urokinase (<i>PLAU</i>) is involved in cell migration, proliferation and tissue remodeling. <i>PLAU</i> upregulation is associated with an increase in aggressiveness, metastasis, and invasion of several cancer types, including breast cancer. In patients, this translates into decreased sensitivity to hormonal treatment, and poor prognosis. These clinical findings have led to the examination of <i>PLAU</i> as a biomarker for predicting breast cancer prognosis and therapy responses. In this study, we investigated the functional ability of <i>PLAU</i> to act as an oncogene in breast cancers by modulating its expression using CRISPR-deactivated Cas9 (CRISPR-dCas9) tools. Different effector domains (e.g., transcription modulators (VP64, KRAB)) alone or in combination with epigenetic writers (DNMT3A/3L, MSssI) were fused to dCas9 and targeted to the <i>PLAU</i> promoter. In MDA-MB-231 cells characterized by high <i>PLAU</i> expression downregulation of <i>PLAU</i> expression by CRISPR-dCas9-DNMT3A/3L-KRAB, resulted in decreased cell proliferation. Conversely, CRISPR-dCas9-VP64 induced <i>PLAU</i> upregulation in low <i>PLAU</i> expressing MCF-7 cells and significantly increased aggressiveness and invasion. In conclusion, modulation of <i>PLAU</i> expression affected metastatic related properties of breast cancer cells, thus further validating its oncogenic activity in breast cancer cells.