Purine-rich element binding protein alpha: a DNA/RNA binding protein with multiple roles in cancers

Abstract

Proteins that bind to DNA/RNA are typically evolutionarily conserved with multiple regulatory functions in transcription initiation, mRNA translation, stability of RNAs, and RNA splicing. Therefore, dysregulation of DNA/RNA binding proteins such as purine-rich element binding protein alpha (PURα) disrupts signaling transduction and often leads to human diseases including cancer. PURα was initially recognized as a tumor suppressor in acute myeloid leukemia (AML) and prostate cancer (PC). Most recently, several studies have revealed that PURα is dysregulated in multiple cancers, such as breast cancer (BC) and esophageal squamous cell carcinoma (ESCC). The oncogenic or tumor-suppressive functions of PURα are realized via regulating RNA/protein interaction, mRNA translation, formation of stress granules (SGs), and transcriptional regulation of several oncogenes and tumor suppressors. Although DNA/RNA binding proteins are hardly targeted, novel strategies have been applied to identify compounds targeting PURα and have demonstrated promising anti-tumor efficacy in the preclinical study. The present review summarizes the most recently discovered critical roles of PURα in various cancer types, providing an overview of the biomarker and therapeutic target potential of PURα for patients with cancer.

Keywords: Biomarker; Cancer; DNA/RNA binding protein; PURα.

Fig. 1

Schematic representation of PURα protein structure The PURα protein contains the glycine-rich, PUR, and glutamine-glutamate-rich domains. The N-terminal glycine-rich domain is involved in protein-protein interaction. The PUR domain is critical for DNA/RNA binding which includes a psycho motif for interaction with pRb protein. The glycine-rich domain is potentially pivotal for the transcriptional activation function of the PURα protein

Fig. 2

Schematic representation of molecular mechanisms driving dysregulation of PURα expression and activity In the nucleic fraction, the PURα mRNA level is regulated by gene deletion and transcription factors (PURα, IRFs, and E2F1). After translation, the activity of nucleic localized PURα protein is regulated by the direct binding of AGPG, PURβ, and HNRNPK in cancer cells. In the cytoplasmic fraction, PURα protein interacts with TM4SF1-AS1 and YB1, organizing stress granules, and showing anti-apoptosis activity in cancer cells

Fig. 3

PURα protein organization and signaling networks in cancers Cancer-relevant PURα interacting proteins and the direct downstream target RNA and DNA are shown. In the nucleic fraction, PURα transcriptionally activates or represses target gene expression via directly binding to DNA or forming complexes with transcription factors or CDK2/CyclinA. In the cytoplasm fraction, PURα organizes the stress granules to activate the MAPK pathway. PURα also binds to 3’UTR of IGFBP3 mRNA to promote translation