Abstract 4742: Investigating the crosstalk between metabolic reprogramming and epigenetic modifications in bone metastatic prostate cancer

Abstract Prostate cancer (PCa) is the second leading cause of cancer-related deaths in the United States. PCa is heavily influenced by the androgen receptor (AR). Throughout disease progression, AR overrides treatment efforts to promote proliferation and survival, often leading to metastatic disease, at which point the management of the disease becomes challenging. Approximately 80% of metastatic disease occurs in the bone, which is the most common site of PCa metastasis. Studies have shown that metabolic activity in the bone microenvironment is crucial, and metabolic reprogramming is required to support the functional requirements of cancer cells, such as continued proliferation. In PCa, increased lipid metabolism plasticity, dysregulation of glycolysis, and OXPHOS dysfunction are linked to worse prognosis. We have also learnt that reprogramming can influence, and be influenced by, epigenetic modification. We performed global proteomic and transcriptomic analyses across five patient-derived xenograft models established from patients with metastatic disease, revealing significant concordance in metabolic processes. Validation studies using Western blot confirmed our results from the mass spectrometry proteomic data. FASN and LDHA protein expression were consistent with gene expression. Next, we determined the implications of FASN inhibition on cell proliferation (live-cell imaging, Incucyte) and metabolism (Cell Titre Glo, which measures cell metabolism by quantifying adenosine triphosphate (ATP) present in all metabolically active cells) in the bone metastatic C4-2B cell line. We observed decreased proliferation. At the molecular level, we observed decreased expression of AR, ZEB1, LDHA, and EZH2. These observations were not observed in the LNCaP (non-bone metastatic model) cell line. Ongoing studies will provide more insight into the cross-talk between AR signaling, EZH2, and metabolic reprogramming in bone metastasis of prostate cancer. Citation Format: Madison Aust, Abbas Jawadwala, Ephraim Jeremiah Gardner, Surendra Gulla, Tej K. Sharma, Remi M. Adelaiye-Ogala.. Investigating the crosstalk between metabolic reprogramming and epigenetic modifications in bone metastatic prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4742.