Targeting TRIM28-mediated Metabolic-Epigenetic Crosslink to Treat Metastatic Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer associated with poor survival rates. Metastatic CRPC exhibits increased reliance on glycolysis. Elevated glucose metabolism not only provides glycolytic intermediates for biomolecule synthesis but also accumulates end-product lactate. Recently, lactate was shown to contribute to a novel epigenetic alteration, known as histone lysine lactylation (KLA) that aberrantly activates transcription program in cancer. However, the mechanism underlying metabolic switch and the role of histone KLA in metastatic CRPC remain unexplored. We previously published that TRIM28 gene expression is aberrantly upregulated in metastatic CRPC. Based on the publicly available data from patient specimen, prostate tumor with high TRIM28 levels display signi?cant enrichment of glycolysis geneset. Our exciting preliminary data revealed that knockdown or overexpression of TRIM28 affect the level of histone KLA. IHC staining indicated that TRIM28 and H3K18La protein level are both upregulated in metastatic PCa tissue. Lastly, we showed that antisense-oligonucleotide (ASO) targeting TRIM28 for degradation remarkably inhibit PCa growth. We hypothesize that TRIM28 regulates histone lactylation via metabolic reprogramming in metastatic CRPC. We propose to determine whether TRIM28 promotes glycolysis and glycolysis-derived lactate by genetically engineering TRIM28 in two independent CRPC cell lines. In addition, we will examine whether TRIM28 regulates the genomic landscape of histone KLA and its downstream transcriptome by performing a CUT&RUN assay and an RNA-seq. Finally, we will evaluate if gene signature in which expression and H3K18La deposition is driven by TRIM28 can predict patient biochemical recurrence and if use of TRIM28-ASO could become a plausible approach to treat CRPC. This is a proof-of-concept study will have high impact, as TRIM28-driven Histone KLA gene signature could serve as a new prognostic marker in PCa and that targeting TRIM28 by ASO lay a foundation for the development of new effective treatment for CRPC.