Reactivation of the dormant tumor suppressor BASP1

MYC is the abbreviation for a cellular protein representing a gene regulator. MYC is a molecular switch converting multiple incoming signals into the activation or suppression of numerous genes that are important for cell growth and metabolism. However, hyperactivation or mutation of MYC leads to abnormal cell growth thereby transforming normal cells into tumor cells. In fact, high MYC protein levels are present in most human tumors classifying MYC as major cancer driver. This is also accompanied by the dysregulation of many MYC-dependent genes. We have previously shown that one of these target genes, termed BASP1, is specifically downregulated by MYC. Moreover, we discovered that BASP1 is switched off in cancer cells because otherwise it would inhibit MYC-induced cell transformation. Reports from other research groups confirmed BASP1 suppression in several human tumors including breast cancer or leukemia. When BASP1 is delivered from outside into these cells, the tumor cells stop growing. Therefore, re-activation of the dormant BASP1 gene in human tumor cells may interfere in general with cancer cell growth and viability. Subsequent analyses of the growth-arrested cancer cells should identify potential new targets for compounds, which could be used as drugs to interfere with growth and viability of MYC-dependent tumor cells. In this project, several biochemical and cell biological approaches are applied. To understand why the BASP1 gene is downregulated in human cancer, the region which controls BASP1 expression is investigated in detail. In addition, regulatory mechanisms acting on the BASP1 protein product are investigated. The above mentioned re-activation of silenced BASP1 in human cancer cells is achieved by using a special application of the so-called CRISPR technology, which was originally developed for specific gene editing. The manipulated cells are then investigated to test if they have lost characteristic properties of cancer cells. Moreover, additional proteins that are involved in this tumor suppressive process are identified by a modern DNA sequencing technique termed ChIP-seq, and by mass spectrometry, a physical method to determine the mass and the identity of a protein. The results should deepen our knowledge about molecular mechanisms how aberrantly expressed MYC drives tumor formation in human cells. The developed procedures could be also transferred for testing other MYC-repressed targets with growth inhibiting functions. The elucidation of these principles has the potential to promote the design of novel MYC inhibitors for specific cancer therapy. Apart from the principal investigator and his team, the groups of Marcel Kwiatkowski, Ph.D. (Institute of Biochemistry, University of Innsbruck) for mass spectrometry analyses, and of Zoran Culig, M.D. (Department of Urology, Medical University of Innsbruck) for experimental cancer models, participate in this project.