PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E

Abstract It is commonly accepted that cellular protein levels are primarily determined by mRNA levels. However, discordance between protein and mRNA expression has been implicated in many pathologic conditions including oncogenesis. The mechanisms involved in this discordance are complicated and far from understood. In this study, it was observed that the expression levels of poly(C) binding protein 2 (PCBP2) mRNA and protein were diametric in breast normal and cancer cell lines, paraffin-embedded and fresh tissue specimens, consistent with data from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium. Moreover, PCBP2 protein expression was significantly associated with disease progression and poor outcome in patients with breast cancer. Depletion of PCBP2 protein inhibited cell proliferation, colony formation, migration, invasion, and in vivo tumor growth and metastasis. Forced expression of PCBP2 exhibited the opposite effect. Mechanistically, it was demonstrated that PCBP2 3′ untranslated region (3′UTR) was subject to alternative splicing and polyadenylation (APA) in breast cancer tissues and cell lines. Non-full-length 3′UTR PCBP2 transcripts yielded more protein than the full-length 3′UTR transcripts and enhanced the oncogenic and metastatic capacities of human breast cancer cells. Furthermore, UFD1 and NT5E were identified as genes downstream of PCBP2. PCBP2 promoted oncogenicity of breast cancer cells via upregulation of the expression of UFD1 and NT5E by direct binding to their 3′UTR-B portions. Implications: Findings demonstrate that APA of PCBP2 3′UTR contributes to its increased expression with subsequent promotion of breast cancer progression by regulating UFD1 and NT5E. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/1/86/F1.large.jpg.