PTBP3 Modulates of P53 Expression and Promotes Colorectal Cancer Cell Proliferation by Maintaining UBE4A mRNA Stability
Abstract Background Colorectal cancer (CRC) is the most common malignancy worldwide and has become the second leading cause of cancer-related death worldwide. The RNA-binding protein polypyrimidine tract-binding protein 3 (PTBP3) was recently reported to play a critical role in multiple cancers, and its molecular mechanisms involve RNA splicing, 3′ end processing and translation. However, the role of PTBP3 in CRC is unclear. Methods We analyzed the expression levels of PTPB3 using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and clinical tissues. The effect of PTBP3 on CRC cell proliferation was measured by Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry and tumor xenograft assays. A series of experiments were conducted to reveal the mechanisms by which PTBP3 promotes CRC proliferation. Results We showed that PTBP3 was upregulated in CRC and associated with a poor prognosis. Knockdown of PTBP3 in CRC cell lines restricted CRC proliferative capacities in vitro and in vivo. Mechanistically, we found that PTBP3 regulated the expression of the E3 ubiquitin ligase ubiquitination factor E4A (UBE4A) by binding the 3' untranslated region (UTR) of its mRNA, thereby preventing its degradation. We also discovered that UBE4A participated in the degradation of P53, and knockdown of PTBP3 in CRC cell lines increased P53 expression. Overexpression of UBE4A rescued PTBP3 knockdown-induced inhibition of CRC cell proliferation and P53 expression. Conclusions PTBP3 plays an essential role in CRC cell proliferation by stabilizing UBE4A to regulate P53 expression and may serve as a new prognostic biomarker and effective therapeutic target for CRC.