PRP4 Induces Epithelial-Mesenchymal Transition and Drug Resistance in Colon Cancer Cells via Activation of p53.

Salman Ul Islam,Eun-Jung Jin,Jong-Kyung Sonn,Muhammad Bilal Ahmed,Young-Sup Lee

doi:10.3390/ijms23063092

Abstract

Pre-mRNA processing factor 4B (PRP4) promotes pre-mRNA splicing and signal transduction. Recent studies have shown that PRP4 modulates the assembly of actin cytoskeleton in cancer cells and induces epithelial–mesenchymal transition (EMT) and drug resistance. PRP4 displays kinase domain-like cyclin-dependent kinases and mitogen-activated protein kinases, making it capable of phosphorylating p53 and other target proteins. In the current study, we report that PRP4 induces drug resistance and EMT via direct binding to the p53 protein, inducing its phosphorylation. Moreover, PRP4 overexpression activates the transcription of miR-210 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, which activates p53. The involvement of miR-210 in the activation of p53 was confirmed by utilizing si-miR210. si-miR210 blocked the PRP4-activated cell survival pathways and reversed the PRP4-induced EMT phenotype. Moreover, we used deferoxamine as a hypoxia-mimetic agent, and si-HIF to silence HIF-1α. This procedure demonstrated that PRP4-induced EMT and drug resistance emerged in response to consecutive activation of HIF-1α, miR-210, and p53 by PRP4 overexpression. Collectively, our findings suggest that the PRP4 contributes to EMT and drug resistance induction via direct interactions with p53 and actions that promote upregulation of HIF-1α and miR-210. We conclude that PRP4 is an essential factor promoting cancer development and progression. Specific PRP4 inhibition could benefit patients with colon cancer.

Highlights

The cell cycle regulatory protein p53 (TP53) is a well-known tumor-suppressor protein.Disruption of the p53-mediated functions can lead to cancer initiation and/or progression
Among the miRNAs activated by Pre-mRNA processing factor 4B (PRP4), we focused on miR-210, as several previous studies have shown its effects in cell proliferation processes [33–35]
The HT29 cells showed decreased p53 expression (Figure 1A). p53 did not appear in the PC-3 cell lines, even though the mRNA in p53 was visible in the PC-3 cells (Figure 1A and Figure S1B in Supplementary Materials)

Summary

Introduction

The cell cycle regulatory protein p53 (TP53) is a well-known tumor-suppressor protein.Disruption of the p53-mediated functions can lead to cancer initiation and/or progression. Approximately one-half of all human cancers have been associated with mutations in the p53 gene and loss of its function has been observed in over 80% of tumors [1–3]. MicroRNAs negatively regulate posttranscriptional events by binding to the 3 -untranslated region (3 -UTR) of target mRNA at specific sequences. Such a feature results in silencing or degradation of target mRNA [13–15]. Several miRNAs indirectly promote the activation of p53 by targeting its transcripts that encode regulatory proteins. MiR-34a has been reported to enhance transcription and encoded protein levels of p53 by targeting its multiple negative regulators (i.e., MDM4, SIRT1, HDAC1, and YY1) [26]

Methods

Results

Conclusion