1. Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment
- Author
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Giafaglione, Jenna M, Crowell, Preston D, Delcourt, Amelie ML, Hashimoto, Takao, Ha, Sung Min, Atmakuri, Aishwarya, Nunley, Nicholas M, Dang, Rachel MA, Tian, Mao, Diaz, Johnny A, Tika, Elisavet, Payne, Marie C, Burkhart, Deborah L, Li, Dapei, Navone, Nora M, Corey, Eva, Nelson, Peter S, Lin, Neil YC, Blanpain, Cedric, Ellis, Leigh, Boutros, Paul C, and Goldstein, Andrew S
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Urologic Diseases ,Prostate Cancer ,Aging ,Cancer ,Aetiology ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Underpinning research ,Male ,Humans ,Prostate ,Monocarboxylic Acid Transporters ,Cell Differentiation ,Epithelial Cells ,Androgen Antagonists ,Lactates ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - Abstract
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.
- Published
- 2023