Ar-V7 Associated Histone Modification and Metabolic Alterations in Enzalutamide Resistant Prostate Cancer

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


Amassed preclinical and clinical evidence shows that overexpression of androgen receptor (AR) splice variants associates with both primary and secondary resistance towards hormone-ablation therapy and anti-androgen drugs in prostate cancer (PCa), making the clinical benefits of current treatment regimen very limited. Targeting the active AR splice variants has thus become an emerging focus for advanced PCa drug development. AR-V7, a constitutively active variant, is one of the most clinically relevant isoform associating with therapy resistance and poor prognosis. However, mechanisms leading to AR-V7 expression in drug resistant PCa remain under characterized. Epigenetic modulations that may be involved in the splicing events is also largely unknown. In our pilot studies, we found that histone demethylase KDM4 members and methyltransferase DOT1L are highly expressed in C4-2B derived- enzalutamide resistant cells, and their expression correlates with AR-V7. The present proposal will characterize AR splicing events in anti-androgen resistant PCa. The significance of KDM4 and DOT1L in AR-V7 expression, and how their mediated histone modifications regulate AR-V7 at the RNA processing levels will be characterized. On the other hand, whereas AR is crucial in regulating gene expression of several tumor-prone metabolic pathways upon hormone stimulation, how AR-V7 programs tumor metabolism in resistant PCa is not well understood. Given to KDM4A’s role in promoting tumor metabolism via the mitochondria pyruvate gatekeeper, we hypothesized that AR-V7 and KDM4A overexpression leads to distinct metabolic features. We propose that such metabolic alterations may account for the acquired anti-androgen resistance. In this proposal, we will investigate the metabolic profiles of the enzalutamide-resistant PCa cells, and determine the roles of KDM4- and DOT1L-mediated AR-V7 overexpression in tumor metabolism. We will also determine the potential of targeting KDM4 and DOT1L as an alternative strategy to tackle anti-androgen resistance.

Project IDs

Project ID:PC10907-1567
External Project ID:MOST109-2320-B182-015-MY3
Effective start/end date01/08/2031/07/21


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