Abstract 1386: The HSP90 Co-chaperone UNC45A is essential for prostate cancer cell proliferation in vitro and tumor growth in vivo

Abstract UNC45A is a key co-chaperone supporting cancer cell proliferation and tumorigenesis. Interestingly, UNC45A is essential for cancer cells but not for normal cell proliferation. However, the mechanism underlying UNC45A regulatory function is not well studied. We have previously shown that UNC45A functions as a glucocorticoid receptor (GR) co-activator to drive the mitotic kinase NEK7 gene transcription. NEK7 is essential for centrosome separation, mitotic spindle formation, and cytokinesis. GR has been implicated in promoting aggressive prostate tumor growth and resistance to therapy. Indeed, GR upregulation is an established mechanism to bypass the androgen receptor blockade therapy in metastatic-resistant prostate tumors. Here, we tested the hypothesis that UNC45A promotes GR-mediated resistance to hormonal therapy. To this end, we used shRNA-mediated gene silencing to evaluate the impact of UNC45A loss on PC3 prostate tumor progression. Our results show that silencing UNC45A reduces cell proliferation in vitro and tumor growth in vivo. TUNEL analysis and Ki67 staining show that loss of UNC45A triggers DNA damage, reduced cell proliferation, and apoptosis in PC3 tumors grown in the NOD SCID mice model. Immunofluorescence analysis shows a remarkable disorganization of centrosomes in tumor cells expressing UNC45A shRNA. The importance of UNC45A in promoting enzalutamide resistance is being tested in tridimensional spheroid culture and in vivo and will be discussed in this meeting. Overall, our results support the hypothesis that UNC45A is a promising cancer therapeutic target and highlight the need for developing UNC45A small molecule inhibitors to treat aggressive diseases such as prostate and breast cancers. Citation Format: Taoufik LLBIYI, Asif Elahi, Digvijay Singh, Nada Eisa, Yasmeen Jilani, Ahmed Chadli. The HSP90 Co-chaperone UNC45A is essential for prostate cancer cell proliferation in vitro and tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1386.