Kaylie Wenke

Background: In men, prostate cancer is the most common solid tumor and with deaths exceeding 350,000 annually, making it one of the leading causes of cancer-associated death in men.^1,3 Androgen deprivation therapy (ADT) has been the standard of care for initial management of advanced prostate cancer, however, a majority of patients will progress to castration-resistant disease within 2-3 years.^1,2 Castration-resistant prostate cancer (CRPC) is defined as the progression of disease despite chemical or surgical castration.^3,4 The standard of care for CRPC is treatment with docetaxel, an intense antineoplastic agent, or nonsteroidal AR agonists, such as Enzalutamide.^3,4  Y-box binding protein-1 (YB-1) is a transcription factor that regulates expression of target genes by inhibiting DNA damage cell-cycle arrest, and has been shown to be amplified in CRPC.³ This finding could suggest a novel therapeutic target for treatment of CRPC.

Objective: In this narrative review, the mechanisms by which YB-1 suppresses traditional cellular apoptosis, allowing for cancer progression were explored.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2023 using the keywords: “castrate resistant prostate cancer,” “prostate cancer,” “Y-Box binding protein 1.”

Results: Analysis of public mRNA data sets of prostate samples from normal, prostate cancer (PaC), and CRPC patients revealed YB-1 amplification in CRPC compared to PCa cases.⁵ Tissue microarray sections of prostate specimens were immunostained for YB-1 and analyzed.⁶ Cytoplasmic YB-1 was absent or weak in normal epithelium but seen in 86.3% of carcinomas and was accompanied by nuclear YB-1 staining in 32.1% of cases.⁶ Minimal presence of cytoplasmic YB-1 staining was strongly linked to early biochemical recurrence of PaC, additionally the prognosis of YB-1 positive cancers was particularly poor if nuclear YB-1 staining was seen.⁶ Cancer progression was linked to the interaction of YB-1 with long non-coding RNA (lncRNA) CASC11 to suppress the p53 pathway.⁷ This was confirmed by knockdown of CASC11 increasing p53 and p21 expression, indicating activation of the p53 pathway.⁷ Silver staining of SDS-PAGE gels revealed that CASC11 specifically bound to protein bands ranging from 30 to 150kDa, the primary protein being YB-1, conforming the YB-1/CASC11 relationship inhibits p53 signaling.⁷ The ERK/AKT/mTOR pathway activates YB-1 by phosphorylation.⁸ This was confirmed by treating PaC cells with rhEGF, inducing the activation AKT, ERK and mTOR in PaC cells, also increasing the amount of phosphorylated YB-1.⁸ This effect was inhibited in ERK knockout cells suggesting that EGF activates the AKT/ERK/mTOR pathway and stimulates phosphorylation of YB-1 through the ERK pathway.⁸ Nimotuzumab is a humanized anti-EGF monoclonal antibody that has been approved for treating different cancers.⁹ The discovery that nimotuzumab inhibits EMT through modulation of the Akt/YB-1/AR axis, provides a rationale for the use of nimotuzumab as a potential therapeutic agent in prostate cancer treatment.⁹

Conclusion: YB-1 is amplified in CRPC and its presence is associated with worse patient outcomes. The ERK/AKT/mTOR pathway activates YB-1 by phosphorylation, allowing YB-1 to suppress p53 though CASC11, preventing apoptosis. Nimotuzumab is a potential therapeutic agent for CRPC by preventing activation of YB-1 through inhibition of the AKT pathway.

Works Cited:

1. Vellky JE, Ricke WA. Development and prevalence of castration-resistant prostate cancer subtypes. Neoplasia. 2020;22(11):566-575. doi:10.1016/j.neo.2020.09.002.
2. Lokeshwar SD, Klaassen Z, Saad F. Treatment and trials in non-metastatic castration-resistant prostate cancer. Nat Rev Urol. 2021;18(7):433-442. doi:10.1038/s41585-021-00470-4.
3. Ingrosso G, Bottero M, Becherini C, et al. A systematic review and meta-analysis on non-metastatic castration resistant prostate cancer: The radiation oncologist’s perspective. Semin Oncol. 2022;49(5):409-418. doi:10.1053/j.seminoncol.2022.09.005
4. Morote J, Aguilar A, Planas J, Trilla E. Definition of Castrate Resistant Prostate Cancer: New Insights. Biomedicines. 2022;10(3):689. Published 2022 Mar 17. doi:10.3390/biomedicines10030689
5. Shiota M, Sekino Y, Tsukahara S, et al. Gene amplification of YB-1 in castration-resistant prostate cancer in association with aberrant androgen receptor expression. Cancer Sci. 2021;112(1):323-330. doi:10.1111/cas.14695
6. Heumann A, Kaya Ö, Burdelski C, et al. Up regulation and nuclear translocation of Y-box binding protein 1 (YB-1) is linked to poor prognosis in ERG-negative prostate cancer [published correction appears in Sci Rep. 2018 Aug 21;8(1):12821]. Sci Rep. 2017;7(1):2056. Published 2017 May 17. doi:10.1038/s41598-017-02279-x
7. Sun X, Xin S, Zhang Y, et al. Long non‑coding RNA CASC11 interacts with YBX1 to promote prostate cancer progression by suppressing the p53 pathway [published correction appears in Int J Oncol. 2024 Jan;64(1):]. Int J Oncol. 2022;61(3):110. doi:10.3892/ijo.2022.5400