Introduction:
Cancer cells undergo metabolic rewiring and epigenetic alterations that drive disease progression [1]. However, the role of this crosstalk in therapy resistance in prostate cancer (PCa) remains unclear. Fatty acid uptake and oxidation pathways are consistently upregulated in PCa, with a stronger enrichment in aggressive, treatment-resistant tumours [2, 3]. Epidemiological studies have identified obesity as a contributor to the development and progression of PCa, yet its potential contribution to neuroendocrine differentiation remains poorly defined [4]. Here, we investigated how exogenous fatty acids (FAs) reshape the epigenome, modulate androgen receptor (AR) signalling, and influence neuroendocrine differentiation.
Methods and Results:
To define the role of fatty acids in epigenetic reprogramming, we treated MR42D cells with a panel of FAs and examined AR signalling and neuroendocrine differentiation. Prolonged exposure to either FAs or enzalutamide (ENZ) for eight days produced highly concordant transcriptional profiles, marked by suppression of AR signalling and induction of neuroendocrine gene programmes. Notably, the transcription factor ELF3, an AR corepressor, emerged as one of the most strongly upregulated transcripts. Co-immunoprecipitation confirmed direct binding between ELF3 and AR, suggesting its active involvement in neuroendocrine lineage plasticity.
Consistently, ELF3 protein expression progressively increased with advancing PCa cell models, reaching its highest level in NCI-H660 cells. Clinical RNA-seq (GSE197780) showed ELF3 upregulation after neoadjuvant ENZ, and Beltran’s clinical cohort confirmed higher ELF3 in neuroendocrine compared to adenocarcinoma PCa [5]. Motif analysis of published ATAC-seq data from MR42D and NCI-H660 cells indicated ELF3 occupancy at regulatory open chromatin regions of neuroendocrine genes. Moreover, ELF3 knockdown using siRNA reduced neuroendocrine marker expression and impaired growth of MR42D cells, as assessed by Incucyte®.
Conclusions:
Our findings establish a mechanistic link between fatty acid metabolism, epigenetic remodelling, and lineage plasticity in PCa. We show that exogenous fatty acids repress AR signalling and promote neuroendocrine differentiation through ELF3 upregulation. These results highlight ELF3 as a key mediator of therapy resistance and disease progression. Ongoing studies using C13-labelled fatty acids, ATAC-seq, and ChIP-seq will further define the chromatin-level mechanisms driving this phenotype. Targeting fatty acid metabolism and ELF3 may help delay or prevent castration-resistant and neuroendocrine PCa.