Regulation of P53 signaling in breast cancer by the E3 ubiquitin ligase RNF187.

Abstract

The tumor suppressor P53 plays critical role in preventing cancer. P53 is rarely mutated and remains functional in luminal-type breast cancer(1). According to current knowledge, wild-type P53 function is tightly controlled by posttranslational modifications, such as ubiquitination. Several ubiquitin ligases have been shown to regulate P53 ubiquitination and protein stability. Here, we report that RNF187, a RING family ubiquitin ligase, facilitates breast cancer growth and inhibits apoptosis by modulating P53 signaling. RNF187 expression was elevated in breast cancer and correlated with breast cancer survival only in the P53 wild-type groups. Bioinformatic analysis showed that the expression of RNF187 was negatively correlated with the expression of P53 target genes, such as IGFBP3 and FAS, in breast cancer. RNF187 depletion inhibited breast cancer growth and facilitated cell death. RNA sequencing analysis indicated that RNF187 could be an important modulator of P53 signaling. Further experiments showed that RNF187 interacts with P53 and promotes its degradation by facilitating its polyubiquitination in breast cancer cells. Interestingly, the in vitro ubiquitin assay showed that RNF187 can directly ubiquitinate P53 in a manner independent of MDM2. These findings reveal a novel direct P53 regulator and a potential therapeutic target for breast cancer.

• Authors: Xin Li, Zhiguo Niu, Chen Sun, Shu Zhuo, Huijie Yang, Xiao Yang, Yun Liu, Cheng Yan, Zhongbo Li, Qi Cao, Guimei Ji, Yinlu Ding, Ting Zhuang, Jian Zhu
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 2 Pg. 149 (02 14 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35165289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Trans-Activators
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins c-mdm2
• RNF187 protein, human
• Ubiquitin-Protein Ligases

Topics

• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Female
• Humans
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Trans-Activators (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Ubiquitination