*Article* **Exploiting Interdata Relationships in Prostate Cancer Proteomes: Clinical Significance of HO-1 Interactors**

**Sofia Lage-Vickers 1,2, Pablo Sanchis 1,2, Juan Bizzotto 1,2, Ayelen Toro 1,2, Agustina Sabater 1,2, Rosario Lavignolle 1,2, Nicolas Anselmino 3, Estefania Labanca 3, Alejandra Paez 1,2, Nora Navone 3, Maria P. Valacco 1,2, Javier Cotignola 1,2, Elba Vazquez 1,2 and Geraldine Gueron 1,2,\***


**Abstract:** Prostate cancer (PCa) cells display abnormal expression of proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown the anti-tumoral role of heme oxygenase 1 (HO-1) in this disease. In this work, we undertook a mass spectrometry-based proteomics study to identify HO-1 molecular interactors that might collaborate with its modulatory function in PCa. Among the HO-1 interactors, we identified proteins with nuclear localization. Correlation analyses, using the PCa GSE70770 dataset, showed a significant and positive correlation between *HMOX1* and 6 of those genes. Alternatively, *HMOX1* and *YWHAZ* showed a negative correlation. Univariable analyses evidenced that high expression of *HNRNPA2B1, HSPB1, NPM1, DDB1, HMGA1, ZC3HAV1,* and *HMOX1* was associated with increased relapse-free survival (RFS) in PCa patients. Further, PCa patients with high *HSPB1/HMOX1*, *DDB1/HMOX1*, and *YWHAZ/HMOX1* showed a worse RFS compared with patients with lower ratios. Moreover, a decrease in RFS for patients with higher scores of this signature was observed using a prognostic risk score model. However, the only factor significantly associated with a higher risk of relapse was high *YWHAZ*. Multivariable analyses confirmed *HSPB1*, *DDB1*, and *YWHAZ* independence from PCa clinic-pathological parameters. In parallel, co-immunoprecipitation analysis in PCa cells ascertained HO-1/14-3-3ζ/δ (protein encoded by *YWHAZ*) interaction. Herein, we describe a novel protein interaction between HO-1 and 14-3-3ζ/δ in PCa and highlight these factors as potential therapeutic targets.

**Keywords:** *YWHAZ*; *HMOX1*; prostate cancer; proteomics; transcriptomics; protein interactions
