Reprogramming of Isocitrate Dehydrogenases Expression and Activity by the Androgen Receptor in Prostate Cancer

Abstract

Mutations of the isocitrate dehydrogenase genes <i>IDH1</i> and <i>IDH2</i>, key enzymes involved in citrate metabolism, are important oncogenic events in several cancer types, including in 1%-3% of all prostate cancer cases. However, if <i>IDH1</i> and other IDH isoforms are associated with prostate cancer progression, as well as the regulatory factors controlling their expression and activity, remain mostly unknown. Using publicly available datasets, we showed that prostate cancer harbors the highest <i>IDH1</i> expression across the human cancer spectrum and that <i>IDH1</i> expression is altered during prostate cancer progression. We showed that the androgen receptor (AR), a key oncogene in prostate cancer, controls multiple IDH isoforms in both <i>in vitro</i> and <i>in vivo</i> models, predominantly positively regulating <i>IDH1</i>. Chromatin immunoprecipitation experiments confirmed the recruitment of AR at several regulatory regions of <i>IDH1</i> and enzymatic assays demonstrated that AR significantly induces IDH activity. Genetic blockade of <i>IDH1</i> significantly impaired prostate cancer cell proliferation, consistent with IDH1 having a key function in these cancer cells. Importantly, knockdown of <i>IDH1</i> blocked the AR-mediated induction in IDH activity, indicating that AR promotes a mitochondrial to cytoplasmic reprogramming of IDH activity. Overall, our study demonstrates that <i>IDH1</i> expression is associated with prostate cancer progression, that AR signaling integrates one of the first transcriptional mechanisms shown to regulate <i>IDH1</i>, and that AR reprograms prostate cancer cell metabolism by selectively inducing extra-mitochondrial IDH activity. IMPLICATIONS: The discovery that AR reprograms IDH activity highlights a novel metabolic reprogramming necessary for prostate cancer growth and suggests targeting IDH activity as a new therapeutic approach for prostate cancer treatment.