Knockdown of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) enhances tumorigenesis both in vivo and in vitro in bladder cancer

Abstract

Bladder cancer is the most common tumor of the urinary tract. Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, has been observed to be frequently amplified in bladder cancer. However, the role of 14-3-3ζ in various types of cancer is controversial. With reproduction of The Cancer Genome Atlas database, we searched the correlation of YWHAZ expression with survival outcomes of multiple cancers in silico. Our results revealed that only in bladder cancer was there a positive survival trend with YWHAZ overexpression. To study its role in bladder cancer, YWHAZ was successfully downregulated by lentivirus in 5637 and T24 cells. MTT and colony-formation assays showed that YWHAZ downregulation increased cell proliferation. Wound healing and Transwell assays showed that YWHAZ downregulation enhanced cell migration and invasiveness. FACS analysis showed that YWHAZ induced cell cycle arrest, but not apoptosis. A xenograft tumor model revealed that YWHAZ knockdown enhanced tumor growth. Gene set enrichment analysis confirmed that the cell cycle pathway plays a vital role in the function of the YWHAZ gene. In conclusion, knockdown of YWHAZ promoted both in vitro and in vivo tumorigenesis in bladder cancer and may be a novel biomarker for bladder cancer deserving further study.

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

“…YWHAZ amplification is also reported to be clinically significant in other cancer types, including breast , prostate , lung , and oral cancers. Although YWHAZ has also been reported to act as a tumor suppressor during bladder cancer development , our results consistently show that YWHAZ overexpression negatively regulates apoptosis, enabling cellular adaptation to the presence of chemotherapeutic drugs. In contrast to anti‐apoptotic effects, other proteins participating in diverse functions/pathways within cells were found to be upregulated along with YWHAZ overexpression (see supplementary material, Tables S3 and S4).…”

The clinical and prognostic significance of YWHAZ in non‐small–cell lung cancer patients: Immunohistochemical analysis

“…In addition, YWHAZ overexpression was also found to serve as a predictor for poor prognosis in ovarian cancer, 14 gastric cancer, 23 tongue squamous cell carcinoma, 25 prostate cancer, 26 and breast cancer. 29,30 However, no correlation between YWHAZ expression and prognosis was observed in bladder cancer patients 31 and hepatocellular carcinoma patients. 32 The above result showed that YWHAZ expression was associated with lymph node metastasis and present distant metastasis in NSCLC patients, and several published reports showed YWHAZ played important role in regulating tumor cell metastasis.…”

miRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer

“…One interesting thought could be that in TNBCs that overexpress PGRMC1, it could be enhancing the transcription of CCND1 even in tumors that lack ER and PR making it a potential target in TNBCs. The YWHAZ gene has been described in multiple cancers including non-small lung cancer ( 101 ), hepatocellular carcinoma ( 102 ), gastric cancer ( 103 ), bladder cancer ( 104 ), and in breast cancers ( 105 ). Overexpression of YWHAZ in breast cancers has been associated with chemoresistance to anthracyclines particularly associated with metastatic recurrence ( 105 ).…”