Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.
Nature cell biology. 2023 Dec 04 [Epub]
Jenna M Giafaglione, Preston D Crowell, Amelie M L Delcourt, Takao Hashimoto, Sung Min Ha, Aishwarya Atmakuri, Nicholas M Nunley, Rachel M A Dang, Mao Tian, Johnny A Diaz, Elisavet Tika, Marie C Payne, Deborah L Burkhart, Dapei Li, Nora M Navone, Eva Corey, Peter S Nelson, Neil Y C Lin, Cedric Blanpain, Leigh Ellis, Paul C Boutros, Andrew S Goldstein
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA., Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA., Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA., Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA., Laboratory of Stem Cells and Cancer, WEL Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium., Department of Mechanical & Aerospace Engineering, University of California, Los Angeles, Los Angeles, CA, USA., Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA., University of Washington, Seattle, WA, USA., Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, USA. .