PPM1G and its diagnostic, prognostic and therapeutic potential in HCC (Review)

Abstract

Global statistics indicate that hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer‑related death. Protein phosphatase Mg²⁺/Mn²⁺ dependent 1G (PPM1G, also termed PP2Cγ) is one of the 17 members of the PPM family. The enzymatic activity of PPM1G is highly reliant on Mg²⁺ or Mn²⁺ and serves as a dephosphorylation regulator for numerous key proteins. PPM1G, functioning as a phosphatase, is involved in a number of significant biological processes such as the regulation of eukaryotic gene expression, DNA damage response, cell cycle and apoptosis, cell migration ability, cell survival and embryonic nervous system development. Additionally, PPM1G serves a role in regulating various signaling pathways. In recent years, further research has increasingly highlighted PPM1G as an oncogene in HCC. A high expression level of PPM1G is closely associated with the occurrence, progression and poor prognosis of HCC, offering notable diagnostic and therapeutic value for this patient population. In the present review, the regulatory role of PPM1G in diverse biological processes and signaling pathway activation in eukaryotes is evaluated. Furthermore, its potential application as a biomarker in the diagnosis and prognosis evaluation of HCC is assessed, and future prospects for HCC treatment strategies centered on PPM1G are discussed.

Keywords: biomarkers; diagnosis; hepatocellular carcinoma; liver fibrosis; prognosis; protein phosphatase Mg2+/Mn2+ dependent 1G; therapeutic.

Figure 1

Schematic of PPM1G production. PPM1G, protein phosphatase Mg²⁺/Mn²⁺ dependent 1G. SMN, survival of motor neurons; snRNP, small nuclear ribonucleoprotein.

Figure 2

Regulatory role of PPM1G in a variety of biological processes. (A) PPM1G can dephosphorylate the T-loop of CDK9 or bind with HEXIM1 and 7SK RNA to create a 7SK-PPM1G snRNP complex. This process releases P-TEFb from the 7SK snRNP complex, thereby reactivating gene transcription elongation. (B) PPM1G can target and dephosphorylate 4E-BP1, and the dephosphorylated 4E-BP1 can then bind to the cap-binding subunit, eIF4E, in the eIF4F complex, which is subsequently isolated from the cap initiation complex, leading to a 'pause' in the protein translation process. (C) When ionizing radiation induces DNA damage, PPM1G is recruited to the DNA damage sites marked by phosphorylated H2AX. Subsequently, ATM phosphorylates and activates PPM1G. The activated PPM1G then targets and dephosphorylates the deubiquitinating enzyme, USP7S, leading to a series of cascading reactions, including a decrease in MDM2 levels and an increase in p53 levels. This results in cell cycle arrest, providing time for DNA repair and the restoration of genomic stability. (D) PPM1G can regulate the cell cycle and apoptosis processes in multiple ways: On the one hand, it specifically inhibits the E3 ligase activity of WWP2, promoting the assembly of the WWP2-WWP1 heterodimer complex, thereby maintaining the balance of cell cycle regulatory proteins, p73 and ΔNp73, within the cell. On the other hand, PPM1G can target and dephosphorylate the cell cycle regulatory proteins, RB, p21WAF1/CIP1 and p27Kip1, thereby inhibiting cell cycle progression. (E) The acidic domain of PPM1G can bind to B56δ, forming the PPM1G-B56δ holoenzyme complex, which in turn promotes the retention of PPM1G in the cytoplasm. The accumulation of this complex in the cytoplasm further enhances the specific dephosphorylation of α-catenin by PPM1G, facilitating the proper assembly of α-catenin and β-catenin in cells, and inhibiting cell migration. PPM1G, protein phosphatase Mg²⁺/Mn²⁺ dependent 1G; CDK9, cyclin-dependent kinase 9; HEXIM1, HEXIM P-TEFb complex subunit 1; snRNP, small nuclear ribonucleoprotein; P-TEFb, positive transcription elongation factor b; 4E-BP1, 4E binding protein 1; eIF4E, eukaryotic initiation factor 4E; eIF4F, eukaryotic initiation factor 4F; ATM, ataxia-telangiectasia mutated; USP7S, USP7 deubiquitylation enzyme; MDM2, murine double minute 2; WWP1/2, WW domain containing E3 ubiquitin protein ligase 1/2.

Figure 3

PPM1G-associated signaling pathways. PPM1G, protein phosphatase Mg²⁺/Mn²⁺ dependent 1G; 4E-BP1, 4E binding protein 1; MKK, MAPK kinase; ARF, ADP ribosylation factor; TSC1/2, tuberous sclerosis proteins 1/2; 4E-BP1, 4E binding protein 1; p, phosphorylation.

Figure 4

PPM1G participates in the occurrence and development of hepatocellular carcinoma and liver fibrosis via different pathways. i) In the occurrence and development of HCC, multiple transcription factors and co-activators are activated, promoting the expression of PPM1G. PPM1G can target and dephosphorylate SRSF3, leading to the dissociation of SRSF3 from the pre-mRNA of CASP8 and PRMT1. Consequently, SRSF3 loses its ability to regulate the alternative splicing of these pre-mRNAs, thereby promoting the proliferation and invasion of HCC cells. ii) PPM1G can promote the proliferation of HCC cells by enhancing the expression of GOF mutant p53. iii) PPM1G can target and inhibit WWP2, which leads to the overactivation of the Notch3/HES1 signaling pathway, promoting the development of liver fibrosis. HCC, hepatocellular carcinoma; PPM1G, protein phosphatase Mg²⁺/Mn²⁺ dependent 1G; SRSF3, Ser/arginine-rich splicing factor 3; PRMT1, protein arginine methyltransferase 1; GOF mutant p53, gain-of-function mutant p53; WWP2, WW domain containing E3 ubiquitin protein ligase 2; HES1, hes family bHLH transcription factor 1; CASP8, caspase 8; sh, short hairpin.