The interplay between glutamine metabolism and epigenetics regulates prostate cancer stem cell populations and tumor radioresistance

• Applicants: Professorin Dr. Anna Dubrovska; Jovan Mircetic, Ph.D.; Professor Ben Wielockx, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Hematology, Oncology ; Reproductive Medicine, Urology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416001651

Prostate cancer is one of the most common causes of cancer-related deaths in the male population globally, and the third leading cause of cancer-related deaths among men in Germany. Prostate cancer patients diagnosed with high-risk disease have an increased risk of developing incurable metastatic disease. Radiotherapy is one of the mainstays of curative treatment for prostate cancer; however, local tumor control is often hampered by tumor radioresistance. The local tumor control after fractionated radiotherapy depends on the pre-treatment number of cancer stem cells (CSCs) and their intrinsic radioresistance. We showed that prostate cancer cells could be radiosensitized by glutamine deprivation, which results in DNA damage and oxidative stress. A glutaminolysis-produced α-KG is a critical cofactor for the epigenetic enzymes such as JMJC-containing histone demethylases and DNA demethylases as well as hypoxia-inducible factor (HIF)-prolyl hydroxylases (PHDs) essential for HIFα-hydroxylation and consequent degradation. We found that depleting glutamine deregulates the histone methylation profile of prostate cancer cells and results in the attenuation of CSCs in vitro and in vivo. We also found an interplay between glutamine metabolism, hypoxic signaling and CSC-related pathways. Furthermore, high glutamine concentrations in the blood plasma of prostate cancer patients are significantly associated with a shorter prostate-specific antigen (PSA) doubling time. We also found a significant association between expression levels of GLS and MYC genes, two critical regulators of glutamine metabolism, and progression-free survival in prostate cancer patients treated with radiotherapy. Our findings that glutamine metabolism can induce prostate cancer reprogramming and influence the CSC properties, tumor radioresistance, and clinical outcomes, laid the groundwork for the proposed research. This study aims: (i) to validate the links between glutamine metabolism and prostate cancer stem cells (CSC) and comprehensively analyze potential epigenetic signaling mediators bridging glutaminolysis and stemness; (ii) to decipher the role of reciprocal regulation of glutamine metabolism and hypoxia-inducible signaling for CSC maintenance; (iii) to validate the role of selected regulators and effectors of glutamine metabolism for prostate cancer in vivo growth and radioresistance, and (iv) to analyze the clinical relevance of the identified metabolic and epigenetic regulators. Thus, our study offers an in-depth characterization of the molecular mechanisms mediating the interaction between glutamine metabolism, epigenetic modulators, and CSC populations and might reveal tumor resistance mechanisms and identify new prognostic biomarkers and therapeutic targets for prostate cancer.

• DFG Programme: Research Grants