YWHAZ amplification/overexpression defines aggressive bladder cancer and contributes to chemo‐/radio‐resistance by suppressing caspase‐mediated apoptosis

Abstract

The objective of this study was to characterize the oncogenic actions of a recently identified cancer‐associated gene YWHAZ (also named as 14‐3‐3 ζ/δ) in urothelial carcinomas of the urinary bladder (UCUB). A genome‐wide study revealed YWHAZ to be involved in the amplicon at 8q22.3, and its genetic amplification was detected predominantly in muscle‐invasive bladder cancer (MIBC). Immunohistochemical 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 and STRING network studies suggested involvement of YWHAZ in regulating caspase‐mediated apoptosis. Ectopic expression of YWHAZ in bladder cells with low endogenous YWHAZ levels boosted cell resistance to doxorubicin and cisplatin, as well as to ionizing radiation. Conversely, YWHAZ‐knockdown using specific shRNA in cells with high endogenous YWHAZ levels diminished survival activity, suppressing cell growth and increasing cell death. Our findings confirm the essential role played by YWHAZ in sustaining cell proliferation during chemo/radiotherapy. Treatments based on anti‐YWHAZ strategies may thus be beneficial for UCUB patients overexpressing YWHAZ. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer

“…In this regard, epigenetic silencing of miR-193a could result in upregulation of YWHAZ and tumor invasion in vitro and in vivo . As YWHAZ was previously found to be involved in cancer metastasis ( 24 , 25 ), overexpression of YWHAZ could enhance gastric cancer invasion in vitro and in vivo . Clinically, higher miR-193a methylation, and YWHAZ expression, was observed in patient tissue samples with H. pylori infection, suggesting that H. pylori mediated STAT3 activating might be responsible for this phenomenon.…”

“…Combination of three microRNA databases found that there are 97 common targets with predicted miR-193a binding site. One of the downregulated targets, YWHAZ , which has been previously found to be involved in metastasis ( 24 , 25 ), was chosen for further investigation.…”

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

“…This therapeutic avenue might be combined together with different immunomodulatory drugs, enhancing their effect [ 53 ]. In the case of 14-3-3ζ/δ, Yu et al [ 54 ] reported that immune-associated genes involved in interferon signaling, TLR-4 signaling, inflammasome network, antigen presentation/TCR recognition, and CD28 co-stimulation were found significantly downregulated in patients with urothelial carcinomas of the urinary bladder (UCUBs) presenting YWHAZ amplification/overexpression. However, there is no evidence of YWHAZ immunomodulation in PCa.…”

Development and validation of a novel epigenetic-related prognostic signature and candidate drugs for patients with lung adenocarcinoma

“…Wang et al revealed that TFDP1/E2F1 transcriptional activity played an important role in NSCLC [ 37 ]. YWHAZ (also named 14-3-3ζ), acts as a major hub protein for many signal transduction pathways [ 38 , 39 ]. YWHAZ was frequently shown to be upregulated in several types of cancers, and its overexpression was often correlated with unfavorable prognosis of cancer patients [ 40 – 43 ].…”