Wednesday, October 9, 2024
10/9/2024
PROJECT SUMMARY This proposal builds upon our discovery in the previous funding period of a novel pathway in prostate cancer cells that integrates androgen signaling with ADP-ribosylation. The pathway has four key components, the androgen receptor (AR), Parp7, Parp9 and Dtx3L. We found that the pathway involves AR induction of Parp7 and multi-site mono-ADP-ribosylation by Parp7, on cysteines in the AR amino-terminal domain. In this pathway, Parp7 acts as an ADP-ribose writer and Parp9 serves as an ADP-ribose reader, and the outcome of these reactions is androgen- dependent assembly of an AR-Dtx3L/Parp9 complex and regulation of AR activity as a transcription factor. With this knowledge base, we are positioned to tackle important questions on how the pathway drives biological effects in prostate cancer cells, and whether Parp7 is an actionable target in models that include castrate-resistant prostate cancer where there is an unmet clinical need. In Aim 1, we will determine how the AR-Parp7 pathway and mono-ADP- ribosylation regulate tumorigenesis in prostate cancer cells using structure-function experiments that interrogate the contributions of each of the four components. Since AR is the only known Parp7 substrate in prostate cancer cells, we will define the ADP-ribosyl-proteome in prostate cancer cells to identify additional, AR-independent pathways, by which Parp7 regulates prostate cancer cells. In Aim 2 we will determine the molecular basis for ADP-ribose writing and reading on the AR-Parp7 pathway. Parp7 ADP-ribosylation of AR is specific for androgen-bound AR, and we have a strategy in place to determine how the agonist conformation of AR generates sites that are permissive for ADP-ribosylation. AR will be used as a model to study the reader function of Parp9 macrodomains, in particular, the features that are important for selectivity. In Aim 3 we determine the vulnerability of prostate cancer cells to a first-in-class Parp7 inhibitor, and test whether the inhibitor can prostate growth and metastasis. Our study will benefit from significant contributions from a team of national and international scientists with expertise in prostate cancer models, proteome-scale mass spectrometry, synthetic peptide chemistry, Parp structural biology, and implementation of Parp inhibitors. Our overall hypothesis is that androgen signaling transduced through Parp7 regulates both genomic and non-genomic pathways, and that selective blockade of Parp7 will inhibit prostate tumorigenesis. If the hypothesis is correct, our work will identify Parp7 as a new therapeutic target in prostate cancer and expand the toolbox of Parp inhibitor-based treatments.
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