ZNF213 negatively controls triple negative breast cancer progression via Hippo/YAP signaling

• Published in: Cancer science Vol. 112; no. 7; pp. 2714 - 2727
• Main Authors: Liu, Yun, Su, Peng, Zhao, Wuchen, Li, Xin, Yang, Xiao, Fan, Jianing, Yang, Huijie, Yan, Cheng, Mao, Lanzhi, Ding, Yinlu, Zhu, Jian, Niu, Zhiguo, Zhuang, Ting
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.07.2021; John Wiley and Sons Inc
• Subjects: Breast cancer; Cancer therapies; Carcinogenesis; Cell migration; Cloning; Connective tissue growth factor; CYR61 protein; Estrogens; Gene expression; Genomics; Growth factors; Health aspects; Kinases; Lysine; Medical prognosis; Original; Phosphorylation; Plasmids; Prognosis; Protein turnover; Proteins; Proteolysis; Reagents; stability; ubiquitin; Ubiquitination; Wound healing; YAP; Yes-associated protein; ZNF213; YAP; breast cancer; ZNF213; stability; ubiquitin
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14916

Breast cancer is one of the most commonly diagnosed malignancies worldwide, while the triple negative breast cancer (TNBC) is the most aggressive and virulent subtype in breast cancers. Compared with luminal type breast cancers, which could be well controlled by endocrine treatment, TNBC is worse in prognosis and lack of effective targeted therapy. Thus, it would be interesting and meaningful to identify novel therapeutic targets for TNBC treatments. Recent genomic data showed the activation of Hippo/YAP signaling in TNBC, indicating its critical roles in TNBC carcinogenesis and cancer progression. Hippo/YAP signaling could subject to several kinds of protein modifications, including ubiquitination and phosphorylation. Quite a few studies have demonstrated these modifications, which controlled YAP protein stability and turnover, played critical role in Hippo signaling activation In our current study, we identified ZNF213 as a negative modifier for Hippo/YAP axis. ZNF213 depletion promoted TNBC cell migration and invasion, which could be rescued by further YAP silencing. ZNF213 knocking down facilitated YAP protein stability and Hippo target gene expression, including CTGF and CYR61. Further mechanism studies demonstrated that ZNF213 associated with YAP and facilitated YAP K48‐linked poly‐ubiquitination at several YAP lysine sites (K252, K254, K321 and K497). Besides, the clinical data showed that ZNF213 negatively correlated with YAP protein level and Hippo target gene expression in TNBC samples. ZNF213 expression correlated with good prognosis in TNBC patients. Our data provided novel insights in YAP proteolytic regulation and TNBC progression. The triple negative breast cancer (TNBC) is the most aggressive and virulent subtype in breast cancers.In our current study, we identified ZNF213 as a negative modifier for Hippo/YAP axis in TNBC. Our data provided novel insights in YAP proteolytic regulation and TNBC progression.