Kimi:

PEST-containing nuclear protein (PCNP) is a 178-amino-acid nuclear protein characterized by the presence of PEST motifs, which are enriched in proline (P), glutamic acid (E), serine (S), and threonine (T). These motifs often serve as signals for rapid protein degradation via the ubiquitin-proteasome system. PCNP is ubiquitinated by the E3 ligase NIRF (Np95/ICBP90-like RING finger protein) and is context-dependent in regulating cell proliferation, migration, and apoptosis in various cancer models. Below is an overview of the research progress on PCNP:

Gene and Protein Structure

PCNP is located on human chromosome 8q24.3, spanning 3,578 bases with 3 exons and 2 introns. It encodes a protein of 178 amino acids with a molecular weight of approximately 21 kDa. The protein contains a PEST sequence, which acts as a proteolytic recognition signal. The degradation of specific proteins via the PEST sequence plays a crucial role in modulating signaling pathways that control cell growth, differentiation, apoptosis, and stress responses. PCNP is primarily degraded through the ubiquitin-proteasome system (UPS) and the calpain pathway. Phosphorylation of threonine and serine residues accelerates its degradation. The N-terminus of PCNP contains a nuclear localization signal (NLS), while the C-terminus contains a nuclear export signal (NES). PCNP shuttles between the nucleus and cytoplasm. Phosphorylation at specific sites can alter its subcellular localization.

Expression and Regulation

In normal tissues, PCNP is widely expressed in various tissues such as the brain, heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas, with particularly high expression in the brain and testes. In cancer tissues, PCNP expression varies across different cancers. For example, PCNP expression is elevated in hepatocellular carcinoma (HCC) tissues compared to adjacent non-tumor tissues and correlates with enhanced proliferation, invasion, and tumorigenicity in vitro and in vivo. In ovarian cancer, PCNP expression is upregulated and positively correlated with Wnt/β-catenin pathway upregulated genes. PCNP expression is also elevated in peripheral blood mononuclear cells of patients with active rheumatoid arthritis.

At the transcriptional level, the transcription factors Sp1 and Sp3 can bind to the PCNP gene promoter region and regulate its expression. At the post-transcriptional level, microRNA-34a can directly target the 3’-untranslated region (3’-UTR) of PCNP mRNA, inhibiting its expression. At the post-translational level, as mentioned earlier, PCNP is ubiquitinated by NIRF and degraded via the UPS. Additionally, PCNP can be phosphorylated and acetylated, which regulate its stability and activity.

Biological Functions

• In cancer: PCNP exhibits dual roles in cancer, acting as both a tumor suppressor and a tumor promoter. In neuroblastoma, PCNP promotes apoptosis via the MAPK pathway and inhibits the pro-survival PI3K/AKT/mTOR pathway, functioning as a tumor suppressor. In lung adenocarcinoma, it is described as a tumor promoter. In ovarian cancer, PCNP accelerates β-catenin nuclear accumulation, activates the Wnt/β-catenin pathway, triggers epithelial-mesenchymal transition (EMT), and promotes ovarian cancer progression. In hepatocellular carcinoma, PCNP expression is upregulated and correlates with enhanced proliferation, invasion, and tumorigenicity. Its cytoplasmic accumulation is associated with higher recurrence rates and poorer survival. In thyroid cancer, PCNP is a novel regulator of proliferation, migration, and invasion. In glioblastoma, NIRF inhibition stabilizes PCNP, enhancing its tumor-suppressive activity. PCNP can also stabilize β-catenin by degrading its ubiquitin ligase β-TrCP, enabling β-catenin/TCF4-driven transcription of oncogenes and promoting EMT in colorectal and ovarian cancers. Under hypoxic stress, PCNP stabilizes HIF-1α by blocking VHL-mediated ubiquitination, driving glycolytic gene expression to support tumor survival. ERK-dependent phosphorylation of PCNP activates PI3K/AKT/mTOR signaling, promoting cell growth and inhibiting autophagy. In the p53 pathway, PCNP facilitates MDM2-mediated ubiquitination of p53 under normal conditions, but DNA damage disrupts this interaction, allowing p53 to activate pro-apoptotic genes and enforce cell cycle arrest via p21. PCNP further suppresses autophagy by stabilizing mTORC1.

• In inflammation: Studies have found that PCNP expression is significantly elevated in peripheral blood mononuclear cells of patients with active rheumatoid arthritis, suggesting that PCNP may be involved in regulating inflammatory responses.

• In angiogenesis: In vitro experiments using human umbilical vein endothelial cells (HUVECs) have shown that PCNP overexpression strongly inhibits endothelial cell proliferation, migration, and tube formation, while PCNP knockdown has the opposite pro-angiogenic effects, positioning PCNP as a novel inhibitor of angiogenesis. Transcriptome analysis indicates that its primary anti-angiogenic mechanism involves suppressing pro-inflammatory signaling pathways such as IL-17, TNF, and NF-κB, which are central to endothelial cell activation.

Interactions with Other Proteins

PCNP interacts with several proteins, including E3 ubiquitin-protein ligase MARCH7, BMI1, TRAM1, and UHRF2. Overexpression of PCNP inhibits cancer cell growth, migration, and invasion by promoting apoptosis. It also interacts with NIRF. NIRF ubiquitinates PCNP as an E3 ligase, controlling its stability and potential role. PCNP may be associated with NIRF in cell cycle regulation. As a NIRF substrate, PCNP may undergo histone post-translational modification regulation similar to p53, thereby altering the activation of transcription factors and the expression of downstream genes.

Research Progress in Diseases

• Cancer: Numerous studies have demonstrated that PCNP is involved in the development of various cancers, such as lung adenocarcinoma, thyroid cancer, ovarian cancer, hepatocellular carcinoma, and neuroblastoma. It influences cancer cell growth, the cell cycle, and autophagy through diverse pathways. For instance, in hepatocellular carcinoma, the PCNP-UHRF2-ErbB3 axis has been identified as a key driver of HCC progression, with cytoplasmic PCNP expression correlating with advanced T stage, clinical stage, and recurrence. In ovarian cancer, PCNP promotes tumor progression by accelerating β-catenin nuclear accumulation and triggering EMT. In neuroblastoma, PCNP mediates proliferation, migration, and invasion via MAPK and PI3K/AKT/mTOR signaling pathways.

• Inflammatory diseases: As mentioned earlier, PCNP expression is elevated in peripheral blood mononuclear cells of patients with active rheumatoid arthritis, indicating its potential involvement in inflammatory responses. This provides a basis for studying its role in inflammation-driven pathologies such as rheumatoid arthritis.

• Angiogenesis-related diseases: In vitro studies suggest that PCNP functions as a negative regulator of angiogenesis. Its anti-angiogenic effects are primarily mediated through the suppression of pro-inflammatory signaling pathways. This makes PCNP a promising therapeutic target for diseases driven by pathological neovascularization, such as retinal neovascularization.

Research Significance and Prospects

PCNP, as a newly identified oncoprotein, is a short-lived nuclear protein containing PEST sequences. Its regulation through ubiquitination and proteasomal degradation has emerged as a potential target for chemotherapy. Research on PCNP helps deepen our understanding of the molecular mechanisms underlying cancer development and progression, providing a scientific basis for cancer diagnosis, treatment, and prognosis. For example, targeting the stability, activation/inhibition, and localization of PCNP may offer novel strategies for precision oncology. Additionally, investigating other nuclear proteins containing PEST motifs holds promise for advancing cancer diagnosis and treatment. In the field of inflammatory diseases, exploring the role of PCNP in inflammation may lead to new therapeutic targets and approaches for inflammatory diseases. In angiogenesis-related diseases, PCNP’s role as a negative regulator of angiogenesis provides new avenues for treating pathological neovascularization disorders. However, the molecular mechanisms underlying PCNP’s roles in tumorigenesis and its precise biological functions as a nuclear protein remain incompletely understood. Further research is needed to address questions such as how PCNP contributes to protein degradation and the roles of PCNP-associated macromolecules. This will facilitate the development of effective PCNP-based diagnostic and therapeutic strategies and accelerate their clinical application.