HO-1 Nuclear Interactome Implications in Neuroendocrine Transdifferentiation in Prostate Cancer

Neuroendocrine prostate cancer (NEPC) is characterized by androgen receptor (AR) independence and poor response to conventional therapies, highlighting the need to unveil the molecular mechanisms behind NEPC. We previously showed that heme oxygenase 1 (HO-1, encoded by HMOX1) translocates to the nucleus exerting unexplored non-canonical functions. The present study delineates the nuclear interactome of HO-1, revealing a potential mechanism that impairs NEPC establishment. Through a proteomics approach integrated with bioinformatics analyses, we identified eleven novel nuclear interactors of HO-1. Unsupervised clustering analyses of RNA-seq data from prostate cancer (PCa) patient-derived xenografts (MDA PCa PDXs) and clinical cohorts demonstrated high expression of three HO-1 interactors (ILF3, SAFB, BCLAF1, and DDX17) in NEPC samples, with concomitant HMOX1 under-expression. Spatial transcriptomics in a mixed-histology tumor confirmed enrichment of the interactors in the NEPC foci. To better understand the link between HO-1 and NEPC, we established and characterized an in vitro model of NE transdifferentiation in PCa cell lines using forskolin to induce phenotypic reprogramming. HO-1 upregulation in transdifferentiated cells significantly attenuated the expression of NE markers and triggered a morphological shift, restoring epithelial phenotypes. This work identifies for the first time HO-1 nuclear interactome association with NEPC, where the HMOX1-ILF3-SAFB-BCLAF1-DDX17 print emerges as a useful marker for disease stratification.