Exploring the activity of transcription factor Sp1 associated to mesenchymal epithelial transition as a therapeutic target of osteosarcoma

Abstract

The Sp1 transcription factor is an important element in the development of osteosarcoma, the most common primary malignant bone tumor in children and adolescents, characterized by the rapid development of metastases. The genes encoding metalloproteinases, proteins associated with the mesenchymal epithelial transition (EMT), apoptosis and DNA repair are recognized targets of Sp1 that participate in the initiation, promotion, progression and metastasis of various types of cancer. EMT is a widespread and important biological process that relies on a genetically induced change to a mesenchymal phenotype of epithelial cells, being one of the major pathways for osteosarcoma regulated by Sp1e and has recently become a focus in the investigation of new therapeutic strategies for cancer. The activity of Sp1 in the regulation of different molecular pathways is the result of post-translational modifications such as acetylation, phosphorylation, glycosylation, SUMOylation and ubiquitination, as well as association with non-coding RNAs and proteins. The objective of this project is to identify genetic and chemical modulators of Sp1 that affect its transcriptional and non-transcriptional activity. The screening of these modulators will be done on a genomic scale using the CRISPR-Cas9 system. From these experiments we expect to identify a combination of therapeutic agents that inhibit the proliferation of osteosarcoma cell lines, via inhibition of activity and reduction of Sp1 levels. Taken together, this may affect DNA repair mechanisms, block cell invasion / migration, and reverse the EMT process, resulting in direct inhibition of cell proliferation or sensitization to classical anticancer drugs such as doxorubicin and cisplatin. (AU)