Abstract 265: YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance via deregulation of caspase-mediated apoptosis

The objective of this study is to characterize the oncogenic roles of a recently identified cancer-associated gene called YWHAZ (also known as 14-3-3 α/ζ ) in urothelial carcinomas of urinary bladder (UCUB). Based on a genomewide study, YWHAZ was found located at the 8q22.3 amplicon and its genetic amplification was predominantly detected in tumors at more advanced stages, muscle-invasive bladder cancer (MIBC). IHC staining confirmed the association of YWHAZ overexpression with higher tumor stages, lymph node/vascular invasion, and mitotic activity. Univariate and multivariate analyses further indicated the prognostic potential of YWHAZ for more aggressive cancer types. Both gene set enrichment analysis (GSEA) and STRING network studies suggest the involvement of YWHAZ in regulating caspase-mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low YWHAZ levels boosted cells becoming more tolerated toward chemical and ionizing radiation treatments. Gene knockdown by specific shRNA in cells with high YWHAZ levels attenuated the survival activity, resulting in cell growth suppression and cell death. Our data confirmed an essential role of YWHAZ in providing survival signals to sustain cell proliferation during chemo- or radio-therapy. Treatments based on anti-YWHAZ strategies may be beneficial for patients with YWHAZ overexpression. Citation Format: Jim Jinn-Chyuan Sheu, Chia-Cheng Yu, I-Hsuan Chen, Praveen Korla, Grace Ko, Chee-Yin Chai, Chien-Fong Li. YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo-/radio-resistance via deregulation of caspase-mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 265.