Roles of PTBP1 in alternative splicing, glycolysis, and oncogensis

Abstract

Polypyrimidine tract-binding protein 1 (PTBP1) plays an essential role in splicing and is expressed in almost all cell types in humans, unlike the other proteins of the PTBP family. PTBP1 mediates several cellular processes in certain types of cells, including the growth and differentiation of neuronal cells and activation of immune cells. Its function is regulated by various molecules, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and RNA-binding proteins. PTBP1 plays roles in various diseases, particularly in some cancers, including colorectal cancer, renal cell cancer, breast cancer, and glioma. In cancers, it acts mainly as a regulator of glycolysis, apoptosis, proliferation, tumorigenesis, invasion, and migration. The role of PTBP1 in cancer has become a popular research topic in recent years, and this research has contributed greatly to the formulation of a useful therapeutic strategy for cancer. In this review, we summarize recent findings related to PTBP1 and discuss how it regulates the development of cancer cells.

Keywords: Polypyrimidine tract-binding protein 1 (PTBP1); Alternative splicing; Glycolysis; M2 isoform of pyruvate kinase (PKM2); Cancer.

Fig. 1

Location, structure, and formation of PTBP1 The PTBP1 gene is located on chromosome 19p13.3 in humans and has one N-terminal nuclear shuttling domain and four repeats of quasi-RNA recognition motif (RRM) domains. NLS: nuclear localization signal

Fig. 2

Functions and regulation of PTBP1 in normal cells PTBP1 functions mainly in neuronal cells, in which it interacts with Pnky, miR-124, PSD-95, and Pbx1. PTBP1 regulates neurogenesis, NMD, transcription of neuronal genes, and tissue repair of neurogenic cells. It also regulates CD5 via alternative polyadenylation and CD40L and IL-2 via the PLCγ1/ERK1/2 and NF-κB pathways. PTBP1 regulates apoptosis via BIM and MCL1. miR-124: microRNA-124; PSD-95: postsynaptic density protein 95; NMD: nonsense-mediated mRNA decay; BIM: BCL-2-like 11; MCL1: myeloid cell leukemia 1; REST: repressor element 1 silencing transcription factor; PLCγ1: phospholipase Cγ1; ERK: extracellular signal-regulated kinase; NF-κB: nuclear factor-κB

Fig. 3

Functions and regulatory roles of PTBP1 in cancer cells PTBP1 plays an important role in glycolysis, proliferation, invasion, apoptosis, and tumorigenesis. It is regulated by the miR-145/c-Myc and AP/β-catenin/c-Myc pathways. PTBP1 increases the transformation of PKM1 to PKM2, which is a crucial process for glycolysis. PKM2 increases the phosphorylation of Beclin-1 and mediates autophagic activation. PTBP1 inhibits the inclusion of an exonic splicing suppressor in exon 4 of the SRSF3 gene. This inhibition leads to the overexpression of SRSF3 and increases the transformation of PKM1 to PKM2. PTBP1 regulates tumorigenesis via CDC42-v1/v2 and regulates apoptosis via MCL1. CDC42: cell division control protein 42 homolog; MCL1: myeloid cell leukemia 1; SRSF3: serine and arginine-rich splicing factor 3; ERK: extracellular signal-regulated kinase; MEK: mitogen-activated protein kinase kinase; GSK-3: glycogen synthase kinase-3; PI3K: phosphoinositide 3-kinase; P: phosphorylation; AP: apigenin