Deciphering the Nuclear Role of Heme Oxygenase-1 in Prostate Cancer: Transcriptional Reprogramming and Neuroendocrine Differentiation

ROCIO SENIUK; AGUSTINA SABATER; GASTON PASCUAL; PABLO SANCHIS; JULIA LECHUGA; JAVIER COTIGNOLA; NICOLAS ANSELMINO; ELBA VAZQUEZ; ESTEFANÍA LABANCA; AYELEN TORO; GERALDINE GUERON

Simposio; 12th Annual Symposium on Global Cancer Research (ASGCR).; 2024

Purpose: This study probes the role of Heme Oxygenase-1 (HO-1) and its nuclear interactors in prostate cancer (PCa). Previous results, demonstrated the anti-tumoral role of HO-1 in PCa and its nuclear translocation, hinting at its potential regulatory roles within the nucleus. Thus, we postulate that HO-1, alongside its interactors, can reprogram PCa cells to a less aggressive phenotype. Methods: From the 11 HO-1 nuclear interacting proteins previously identified, 4 were transcription factors. Using ChIP Atlas we evalauted the binding affinity of these factors to their downstream gene targets. Gene ontology and KEGG pathway analyses were then performed to associate these targets with specific biological processes and pathologies. Additionally, RNA-seq data from patient-derived xenografts (PDXs) at MD Anderson Cancer Center (MDA PCa PDXs) were analyzed to evaluate the clinical relevance of these genes in the context of PCa heterogeneity. These PDXs offer a clinically relevant model due to their representation of the disease’s heterogeneity. We scrutinized the expression of the gene clusters of interest in PDXs, including their association with neuroendocrine (NE) phenotypes. Results: The transcription factors among the HO-1 interactors previously described, were found to bind genes enriched in processes related to histone modification, acetylation, and transcription termination, implicating their role in gene expression regulation. KEGG pathways linked these genes to neurodegenerative diseases (including Parkinson’s, Huntington's, and Alzheimer’s disease), mirroring the neuroendocrine (NE) phenotype in advanced PCa, which typically emerges in advanced stages and is characterized by the transdifferentiation of epithelial cells into NE cells lacking androgen receptor expression.The unsupervised clustering of gene expression from PDXs showed that high expression of these genes is associated with an AR-negative NE histopathology, suggesting a potential for these interactors in prostate cancer subtyping.Conclusion: HO-1 nuclear interactors, especially transcription factors, appear to influence gene transcription associated with NE differentiation and cancer aggressiveness. The therapeutic relevance of modulating HO-1's interaction with its nuclear partners warrants further investigation to ascertain its role in mitigating the NE of PCa