NUCLEAR HO-1 INTERACTORS MIGHT DEFINE A NEUROENDOCRINE SIGNATURE IN PROSTATE CANCER

ROCIO SENIUK; PABLO SANCHIS; JUAN BIZZOTTO; ESTEFANÍA LABANCA; NICOLAS ANSELMINO; SOFIA LAGE VICKERS; GASTON PASCUAL; AGUSTINA SABATER; LAURA LACREU; JULIA LECHUGA; NORA NAVONE; ELBA VAZQUEZ; JAVIER COTIGNOLA; PIA VALACCO; AYELEN TORO; GERALDINE GUERON

Congreso; LXVIII Reunión Anual de la Sociedad Argentina de Investigación Clínica.; 2023

Previous reports have shown that heme-oxygenase 1 (HO-1), an enzyme involved in free heme degradation, has a non-canonical anti-tumor effect in prostate cancer (PCa). It is believed that nuclear HO-1 influences the function of various transcription factors, although unraveling its non-canonical role is an unmet need. Thus, in this work we aimed at identifying HO-1’s nuclear interactors and their association with aggressive PCa. PC3 cells were treated with hemin (80 µM, 24 h), a specific pharmacological HO-1 inducer. Next, nuclear HO-1 immunoprecipitation was performed and proteins were subjected to LC-ESI MS/MS analysis, identifying 11 differential nuclear proteins between control and hemin treated PCa cells (ILF3, ILF2, BCLAF1, SAFB, DDX17, SLC25A5, CASP14, PRDX1, BRIX1, CCDC175 and GPATCH1). To decipher how these factors are associated with the aggressive phenotype of PCa, we interrogated RNA-seq expression data of the MDA-PCa-PDXs series (Prostate Cancer Patient Derived Xenografts Program; MD Anderson Cancer Center), which captures PCa disease heterogeneity. Interestingly, an unsupervised clustering analysis considering the expression of HO-1’s interactors showcased that samples with high expression of these genes derived from neuroendocrine tumors, negative for AR staining. Moreover, a Principal Component Analysis revealed ILF3 as the most relevant HO-1 interactor driving PDXs’ samples variance, which was also associated with a significant decrease in relapse-free survival of PCa patients (GSE70770). Additionally, ChIP-Atlas data analysis evidenced that at least 36% of HO-1 nuclear interactors were reported as potential transcription regulators. Strikingly, KEGG pathways analysis revealed that their regulomes are significantly associated with Huntington disease, highlighting their relevance in neural processes. Overall, these findings suggest that HO-1 and its nuclear interactors may play a relevant role in neuroendocrine PCa.