Abstract
TP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.
Highlights
Kidney cancer is one of the most common tumors of the urinary system[1]
We examined the expression of P53-bound enhancer regions (p53BERs) in seven renal cell carcinoma cell lines and the renal epithelial cell line (HK2) and found that the expression level of P53-bound enhancer regions 2 (p53BER2) was downregulated in all renal cancer cell lines, relative to the normal renal epithelial cell line (HK2) (Fig. 1A)
There was no significant difference in p53BER2 levels between renal cell carcinoma and normal renal epithelial cell lines (Fig. 1A)
Summary
Kidney cancer is one of the most common tumors of the urinary system[1]. According to GLOBOCAN guideline 2018, there were 403,262 new renal cancer cases and 175,098 death cases for renal cancer worldwide in 20181. In the U.S, the corresponding number of the above cases in 2014 was 63,290 and 13,8602. The incidence of kidney cancer has been steadily rising. The tumor protein p53 (TP53) gene is the most common mutant gene in human cancers, in which mutations occur in more than 50% of tumors. In the case of tumors carrying the wild-type TP53 gene, changes in other p53-pathway components are believed to be responsible for its inactivation[5]. The p53 protein, encoded by the TP53 gene, is a transcription factor that can regulate the expression of multiple target genes to mediate the diverse cellular
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