BiolThe doctoral dissertation in the field of Biomedicine and Molecular Medicine will be examined at the Faculty of Health Sciences at Kuopio campus. The public examination will be streamed online.
What is the topic of your doctoral research? Why is it important to study the topic?
By utilising state-of-the-art proteomics methods, the topic of my doctoral research was to identify protein networks of the androgen receptor, the main transcription factor of prostate cancer.
Prostate cancer is the most common cancer in men in the Western world and the second most common cancer in men in Finland. Treatment currently focuses on inhibiting androgen signaling and androgen receptor function. However, diagnosis of prostate cancer is often delayed and despite promising treatment, many cancer cases progress, developing resistance to treatments and become castration-resistant prostate cancer, for which there is no treatment yet. One approach to this problem are androgen receptor-associated proteins, especially those at chromatin, that could serve as potential drug targets and thus open new avenues to the treatment of prostate cancer. However, the protein network associated with the androgen receptor is poorly understood. My dissertation offers new information about the protein network and shows its relevance to androgen signaling through three examples.
What are the key findings or observations of your doctoral research?
As a key finding, we managed to identify hundreds of androgen receptor-associated proteins at chromatin. Several of these proteins had not previously been linked to the androgen receptor or to the biology of prostate cancer. However, a large proportion of them played a well-known role in regulating gene expression. In addition, many members of the androgen receptor-associated protein network had altered expression in the primary prostate cancer compared to normal tissue in patient data. Through the silencing of two members, SMARCA4 and SIM2, and by blocking of SUMOylation, a process that mediates post-translational modification, we showed that the importance of the protein network for androgen signaling is context-dependent. These proteins and processes both activate and inhibit the expression of androgen receptor target genes, participating in signaling pathways that are important for prostate cancer. All three examples also contributed to the growth of castration-resistant prostate cancer cells in the cell model.
How can the results of your doctoral research be utilised in practice?
My dissertation complements the existing knowledge of the function of the androgen receptor, but also provides fundamental knowledge of the proteins that work with the androgen receptor. With further research, this knowledge may be utilised in the development of new drugs, in the development of diagnostics for prostate cancer, and in the planning of more targeted drug treatment. The genome-wide and functional experiments in my doctoral research also provide tools and pathways for determining the role of protein network members in androgen signaling.
What are the key research methods and materials used in your doctoral research?
My dissertation focuses on three different proteome-wide methods: proximity-dependent biotin labeling (BioID), selective chromatin-associated protein isolation (ChiP-SICAP), and rapid immunoprecipitation-based chromatin protein identification (RIME). BioID relied on the expression of fusion protein, but managed to identify both known proteins and proteins that had not previously been associated with the androgen receptor. ChIP-SICAP and RIME, on the other hand, are based on crosslinking chromatin and related proteins together before protein isolation. This provides an opportunity to study proteins expressed by the cell itself and thus enabled the use of VCaP cells, a cell model representing the castration resistance prostate cancer. In fact, both chromatin-proteome methods identified a larger androgen receptor protein network compared to BioID, and RIME proved to be more effective in our setting compared to ChIP-SICAP. Many different functional protein groups were identified by all three methods. In addition, several genome-wide methods and functional experiments were used for further studies of protein network members to highlight their role in androgen signaling.
The doctoral dissertation of Kaisa-Mari Launonen, MSc, entitled Chromatin protein networks of the androgen receptor in prostate cancer cells will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Docent Maria Sundvall of the University of Turku, and the Custos will be Professor Jorma Palvimo of the University of Eastern Finland. The public examination will be held in English.
For further information, please contact:
Kaisa-Mari Launonen, MSc, kaisa-mari.launonen@uef.fi, https://uefconnect.uef.fi/en/person/kaisa-mari.launonen/
