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.
Highlights
Breast cancer is the most common cancer in women worldwide, while chemotherapy is one of the major treatment options for breast cancer patients, especially those with refractory cases [1]
RNF187 is elevated in breast tumors and is required for cancer P53 status, we investigated the effect of RNF187 in the luminalgrowth and anti-apoptosis in luminal-type breast cancer type of breast cancer cells with P53 mutation
4 Fig. 1 RNF187 is elevated in breast tumors and is required for cancer cell growth and apoptosis resistance in luminal-type breast cancer
Summary
Breast cancer is the most common cancer in women worldwide, while chemotherapy is one of the major treatment options for breast cancer patients, especially those with refractory cases [1]. P53 signaling was discovered more than 40 years ago and is always activated and subsequently involved in the cell cycle arrest and apoptosis caused by genotoxic drugs, such as cisplatin [2, 3]. The P53 status is an important predictive marker of the chemotherapy response [4]. Mutant P53 can be used as a chemotherapy marker for a basal cell-like breast cancer [5]. Activation of P53 could be investigated as a therapeutic target. Many efforts have been made, targeting P53 signaling is still an immature strategy in breast tumors. It is necessary to further characterize P53 signaling in breast cancer to identify novel therapeutic strategies
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