Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1.

Abstract

TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.

• Authors: Ling Fang, William W Du, Juanjuan Lyu, Jun Dong, Chao Zhang, Weining Yang, Alina He, Yat Sze Sheila Kwok, Jian Ma, Nan Wu, Feiya Li, Faryal Mehwish Awan, Chengyan He, Bing L Yang, Chun Peng, Helen J MacKay, Albert J Yee, Burton B Yang
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 25 Issue 12 Pg. 2195-2208 (12 2018) ISSN: 1476-5403 [Electronic] England
• PMID: 29795334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TP53 protein, human
• Tumor Suppressor Protein p53
• RNA

Topics

• Animals
• Binding Sites (drug effects)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Progression
• Female
• HEK293 Cells
• Humans
• Injections, Intraperitoneal
• Mammary Neoplasms, Experimental (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Molecular Docking Simulation
• Mutation
• Nucleic Acid Conformation
• Proteomics
• RNA (chemistry, genetics, pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)