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Utilizing proteomics to discover novel drug targets in inflammatory conditions and cancer

Recent improvements in mass spectrometric instrumentation and methodology have enabled broader implementation of proteomics, the study of proteins in a large scale, in biomedicine. New sensitive and effective proteomics methods can be applied to identify potential novel drug targets in inflammatory conditions, leukemia and prostate cancer, according to the doctoral dissertation of Joanna Lempiäinen, Master of Science.  The public examination will be held in English at Kuopio Campus and online on 2 October 2020.

State-of-the-art proteomic methods were utilized to identify protein interactions of the glucocorticoid and androgen receptors (GR and AR). The GR and the AR are evolutionarily closely related transcription factors, that drive gene expression by glucocorticoids and androgens by interacting with DNA and other proteins (coregulators). The GR is targeted in inflammatory diseases and leukemia, whereas the AR is a key drug target in prostate cancer.

The protein interactomes of the glucocorticoid and androgen receptors are similar

Effects of different drugs, such as the GR agonist dexamethasone and the AR antagonist enzalutamide, on the protein interactions of the GR and the AR were investigated. Protein interactomes of agonist-bound GR and AR contained both transcription-enhancing coactivators and transcription-inhibiting corepressors, with many interactions being shared between the receptors. Furthermore, antagonist-bound GR and AR exhibited an impaired ability to interact with coregulators. The protein interactions identified in this thesis include proteins that were not previously known to regulate the function of the GR and the AR.

Dexamethasone is a synthetic glucocorticoid that is widely prescribed to treat inflammatory conditions, such as rheumatoid arthritis and asthma, and also in treatments against leukemia. Enzalutamide is an antiandrogen that is used to inhibit the proliferation of prostate cancer.

The protein interactions of the glucocorticoid receptor could be targeted in leukemia

Proteomics were employed in parallel with genome-wide methods to elucidate how the post-translational modification with SUMO (small ubiquitin-related modifier) regulates the function of the GR. SUMOylation-deficient GR had an enhanced ability to interact with chromatin remodelers and it induced chromatin opening at GR-binding sites better than SUMOylated GR. Comparison to previously published data revealed that many of these GR interactors regulate the growth and dexamethasone sensitivity of acute lymphoblastic leukemia cells. These results indicate that SUMOylation could be targeted to increase dexamethasone sensitivity of cancer cells in acute lymphoblastic leukemia.

New epigenetic regulator in prostate cancer was discovered

Prostate cancer is the most common cancer in men in western nations. AR is an important drug target in prostate cancer, because antiandrogens restrict the growth and progression of the cancer. However, prostate cancer can progress to androgen-independent castration-resistant state and continues to grow despite treatments. Especially in these cases new drug targets are needed.

Genome-wide methods were utilized to define the role of BCOR, one of the novel AR-interacting proteins found in this work, in AR signaling in castration-resistant prostate cancer (CRPC) cells. BCOR is recruited to AR chromatin-binding sites and regulates AR target gene expression in CRPC cells in part via regulating monoubiquitination of histone H2A at lysine 119 (H2AK119ub1). Importantly, BCOR depletion attenuated the proliferation and induced apoptosis of CRPC cells. These results suggest that BCOR could be a potential drug target in prostate cancer.

The doctoral dissertation of Joanna Lempiäinen, Master of Science, entitled Protein Interactions of the Glucocorticoid and Androgen Receptors will be examined at the Faculty of Health Sciences, University of Eastern Finland. The Opponent in the public examination will be Docent Biswajyoti Sahu of the University of Helsinki, and the Custos will be Professor Jorma Palvimo of the University of Eastern Finland.

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https://mediabank.uef.fi/A/UEF+Media+Bank/37803?encoding=UTF-8

Lempiäinen, Joanna. Protein interactions of the glucocorticoid and androgen receptors