Decoding the non-canonical functions of HO-1 in prostate cancer: A nuclear perspective and its association with a neuroendocrine signature.

ROCIO SENIUK; AGUSTINA SABATER; PABLO SANCHIS; JUAN BIZZOTTO; GASTON PASCUAL; ESTEFANÍA LABANCA; NICOLAS ANSELMINO; NORA NAVONE; ELBA VAZQUEZ; PIA VALACCO; JAVIER COTIGNOLA; AYELEN TORO; GERALDINE GUERON

San Diego

Congreso; American Association for Cancer Research (AACR) Annual Meeting.; 2024

Previous studies have demonstrated the non-canonical anti-tumor effect of heme-oxygenase 1 (HO-1) in prostate cancer (PCa). Although HO-1 is crucial for free heme degradation, its nuclear expression unveils non-canonical functions beyond its enzymatic function. Understanding the specifics of its non-canonical role remains a critical unmet need. In this study, we identified nuclear interactors of HO-1 and assessed their association with PCa. PCa cells were treated with hemin (80 µM, 24 h), a specific pharmacological inducer of HO-1. Nuclear HO-1 immunoprecipitation and LC-ESI MS/MS analysis identified 11 differential nuclear associated-HO-1 proteins between control and hemin-treated PCa cells (ILF3, ILF2, BCLAF1, SAFB, DDX17, SLC25A5, CASP14, PRDX1, BRIX1, CCDC175, and GPATCH1). Next, we performed an Ingenuity Pathway Analysis (QIAGEN) showing that ILF3 appears as a master regulator of this signature. To assess the clinical relevance of these factors in PCa, we analyzed overall survival (OS), progression-free survival (PFS), relapse free survival (RFS) in multiple PCa datasets (GSE34312, GSE35988, GSE3933, GSE46602, GSE6956, GSE70768, TCGA-PRAD, GSE70770, GSE16560, GSE24136; n=1064). We performed univariable and multivariable analyses for these factors and identified the ones that significantly and independently affected the OS, RFS, PFS. Next, a risk score model was built based on the expression of 9 genes (∑ni=1(Coefi×Expri)) for the GSE70770 dataset using these factors identifying a subpopulation of PCa patients with high-risk of RFS (HR: 7.39 High vs Low score, p