Targeted Inhibition of Tyrosine Kinase-Mediated Epigenetic Alterations to Prevent Resurgence of Castration-Resistant Prostate Cancer.

摘要

Epigenetic alterations leading to the silencing of tumor suppressor genes or activation of oncogenes are underlying causes for metastatic disease. The proposed project set out to identify and quantify novel epigenetic modifications-histone phosphorylations-mediated by oncogenic kinases, that may promote the progression of prostate cancer to androgen independence by using differentially labeled prostate cancer cell lines grown in the presence and absence of androgen. SILAC based mass spectrometry analysis revealed that lysine residues in histones were found to be acetylated at a number of sites and threonine and serine residues were phosphorylated in both androgen dependent and castration resistant prostate cancer cells. Notably, a significant decrease in acetylation of lysine 5 in histone H2B, was observed in androgen deprived cells. Although tyrosine phosphorylation was detected by immunoblotting of histones prepared from prostate cancer cells, specific tyrosine residues were not uncovered by LC-MS/MS analysis. ACK1 and WEE1 tyrosine kinase signaling were found to be some of the major pathways upregulated in prostate cancer cells upon androgen deprivation. Future studies could explore H2BK5Ac, WEE1, and ACK1 substrates as novel biomarkers in prostate cancer.