The development of metastasis is a leading cause of cancer-related death that involves specific changes in the plasma membrane (PM) and nucleus of cancer cells. Elevated levels of membrane lipids, including sphingomyelin, cholesterol, and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), in the PM, contribute to changes in membrane rigidity, lipid raft formation, and actin polymerisation dynamics, processes that drive cell invasion. This review discusses the relationship between well-studied cytoplasmic phosphoinositides and their lesser-known nuclear counterparts, highlighting their functional role in metastatic progression. Nuclear phosphoinositides, particularly PI(4,5)P2, are essential for regulating transcription factors and chromatin organisation, thereby shaping gene expression patterns. We also explore the role of PI(4,5)P2 and its metabolism in cancer cell invasiveness and metastasis, proposing a model in which the dysregulation of cytosolic and/or nuclear PI(4,5)P2 pool triggers malignant transformation. Understanding the PI(4,5)P2-related mechanisms underlying metastasis may provide insights into potential therapeutic targets, paving the way for more effective therapies and improved patient outcomes.

• Keywords
• Biocondensates, Cancer, HPV, Metastasis, Nucleus, Phosphatidylinositol 4,5-bisphosphate,
• MeSH
• Cell Membrane * metabolism   MeSH
• Cell Nucleus * metabolism   MeSH
• Phosphatidylinositol 4,5-Diphosphate * metabolism   genetics   MeSH
• Humans MeSH
• Membrane Microdomains metabolism   MeSH
• Neoplasm Metastasis MeSH
• Neoplasms * metabolism   pathology   genetics   MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Phosphatidylinositol 4,5-Diphosphate * MeSH

The RNA content is crucial for the formation of nuclear compartments, such as nuclear speckles and nucleoli. Phosphatidylinositol 4,5-bisphosphate (PIP2) is found in nuclear speckles, nucleoli, and nuclear lipid islets and is involved in RNA polymerase I/II transcription. Intriguingly, the nuclear localization of PIP2 was also shown to be RNA-dependent. We therefore investigated whether PIP2 and RNA cooperate in the establishment of nuclear architecture. In this study, we unveiled the RNA-dependent PIP2-associated (RDPA) nuclear proteome in human cells by mass spectrometry. We found that intrinsically disordered regions (IDRs) with polybasic PIP2-binding K/R motifs are prevalent features of RDPA proteins. Moreover, these IDRs of RDPA proteins exhibit enrichment for phosphorylation, acetylation, and ubiquitination sites. Our results show for the first time that the RDPA protein Bromodomain-containing protein 4 (BRD4) associates with PIP2 in the RNA-dependent manner via electrostatic interactions, and that altered PIP2 levels affect the number of nuclear foci of BRD4 protein. Thus, we propose that PIP2 spatiotemporally orchestrates nuclear processes through association with RNA and RDPA proteins and affects their ability to form foci presumably via phase separation. This suggests the pivotal role of PIP2 in the establishment of a functional nuclear architecture competent for gene expression.

• MeSH
• Cell Nucleus * metabolism   genetics   MeSH
• Phosphatidylinositol 4,5-Diphosphate * metabolism   MeSH
• Phosphorylation MeSH
• Nuclear Proteins * metabolism   genetics   MeSH
• Humans MeSH
• Cell Cycle Proteins metabolism   genetics   MeSH
• Bromodomain Containing Proteins MeSH
• RNA metabolism   genetics   MeSH
• Transcription Factors * metabolism   genetics   MeSH
• Protein Binding MeSH
• Intrinsically Disordered Proteins * metabolism   genetics   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BRD4 protein, human MeSH Browser
• Phosphatidylinositol 4,5-Diphosphate * MeSH
• Nuclear Proteins * MeSH
• Cell Cycle Proteins MeSH
• Bromodomain Containing Proteins MeSH
• RNA MeSH
• Transcription Factors * MeSH
• Intrinsically Disordered Proteins * MeSH