PPP1R13L drives cervical cancer progression by suppressing p63-mediated PTEN transcription.

PPP1R13L is a conserved inhibitor of p53, selectively regulating a subset of p53 target genes. Previous studies have reported that PPP1R13L promotes cervical cancer progression, yet its precise mechanism remains unclear and warrants further investigation. In this study, we utilized public databases to reveal the correlation between PPP1R13L and tumor progression pathways. Subsequently, we performed functional assays both in vitro and in xenograft models to assess the impact of PPP1R13L on cervical cancer. Our results demonstrate that PPP1R13L promotes cervical cancer cell proliferation, epithelial-mesenchymal transition, cycle progression, and glycolysis via the PTEN/AKT/mTOR pathway. Mechanistically, PPP1R13L regulates the transcription of PTEN through its Ank-SH3 domain interaction with p53 family, p53 and p63. In 293T cells, p53 originally exhibits significantly higher transcriptional activity than p63. However, in cervical cancer-where E6 continuously degrades p53 and p63 is highly expressed-p63 demonstrates a transcriptional activity for PTEN that is comparable to, or even surpasses, that of p53, depending on E6 expression levels. Additionally, in C33A, an HPV-negative cervical cancer cell line, the p53 R273C mutation causes PPP1R13L to exert an opposite effect, and p63 is shown to be inhibited by PPP1R13L independently of p53. Finally, the response elements of PPP1R13L-regulated p53 family target genes were experimentally validated on p63 for the first time. This provides a sequence basis for the selective regulation of p53 family target genes by PPP1R13L. In summary, we underscore the specificity of the PPP1R13L/p63/PTEN axis in cervical cancer and propose that PPP1R13L holds potential as a therapeutic target for cervical cancer treatment.